Novel lincomycin derivatives possessing antimicrobial activity

ABSTRACT

Novel lincomycin derivatives are disclosed. These lincomycin derivatives exhibit antibacterial activity. The compounds of the subject invention may exhibit potent activities against bacteria, including gram positive organisms, and may be useful antimicrobial agents. Methods of synthesis and of use of the compounds are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S patent applicationSer. No. 10/777,455, filed Feb. 11, 2004, which is acontinuation-in-part of U.S. patent application Ser. No. 10/642,807,filed Aug. 15, 2003, and further claims the benefit under 35 U.S.C.§119(e) of U.S. Provisional Application No. 60/479,296 filed on Jun. 17,2003 and of U.S. Provisional Application No. 60/479,502, filed on Jun.17, 2003, the disclosures of which are hereby incorporated by referencein their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to lincomycin derivatives that exhibitantibacterial activity as well as to methods for using such derivatives.

2. State of the Art

Lincomycin is a biosynthetic product that adversely affects growth ofvarious microorganisms, in particular gram positive bacteria. Thecharacteristics and preparation of lincomycin are disclosed in U.S. Pat.No. 3,086,912. A variety of derivatives of lincomycin, which also haveantimicrobial activity, have been prepared. These derivatives include,for example, clindamycin, which is described in U.S. Pat. No. 3,496,163.

Lincomycin derivatives remain attractive targets for antibacterial drugdiscovery. Accordingly, lincomycin derivatives that possessantimicrobial activity are desired as potential antibacterial agents.

SUMMARY OF THE INVENTION

The present invention provides lincomycin derivatives that possessantibacterial activity. In some embodiments, said novel lincomycinderivatives exhibit antibacterial activity against gram positive andanaerobe pathogens. Surprisingly, selected novel lincomycin compoundsdescribed herein exhibit atypical potency against Enterocci species suchas Enterocci faecium and Enterocci faecalis, and/or against fastidiousgram-negative pathogens such as Haemophilus influenzae, when comparedagainst known compounds such as clindamycin.

In one of its composition aspects, this invention is directed to acompound of Formula (I):

wherein:

W is a nitrogen-containing ring:

wherein m is 0, 1, 2, or 3;wherein when m is 2, the nitrogen-containing ring may optionally containa double bond between the 4 and 5 nitrogen-containing ring positions;wherein when m is 3, the nitrogen-containing ring may optionally containone double bond between either the 4 and 5 nitrogen-containing ringpositions or between the 5 and 6 nitrogen-containing ring positions;wherein the nitrogen-containing ring positions are consecutivelynumbered counterclockwise beginning with “1” at the nitrogen;

R¹ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, cycloalkylalkyl, halo, alkylsulfanyl, and substitutedalkylsulfanyl;

R² and R³ are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl,substituted alkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷and the other is absent, or one of R² and R³ is ═CH₂ and the other isabsent;

R⁶ is selected from the group consisting of hydrogen, alkyl,hydroxyalkyl, cycloalkyl, substituted alkyl, iminomethyl, —C(O)O-alkyl,—C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O—substituted aryl,—C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, -(carboxamido)alkyl,(carbamoyl)alkyl, 5-alkyl-[1,3]dioxol-2-one-4-yl-methyl,5-alkyl-[1,3]dioxol-2-one-4-yl-methoxy-carbonyl, or —N(R⁶)— fragment ispart of the amidine, N-cyanoamidine, N-hydroxyamidine, orN-alkoxyamidine structure;

R⁷ is H or alkyl;

R⁹, which can be singly or multiply substituted in the ring on the sameor different carbons, is independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloalkylalkyl, substituted alkenyl,substituted oxygen, substituted nitrogen, halogen, phenyl, substitutedphenyl, alkylsulfanyl, substituted alkylsulfanyl, substitutedarylsulfanyl, heteroarylsulfanylalkyl, heterocyclicsulfanylalkyl,heteroarylsulfanyl, and heterocyclicsulfanyl, propylidene (═CHCH₂CH₃),azido, —(CH₂)_(n)—OH, —(CH₂)_(n)—NR⁴R⁵, and branched chain isomersthereof wherein n is an integer of from 1 to 8 inclusive and R⁴ and R⁵are H or alkyl, alkoxyalkoxy, aryl, substituted aryl, alkenyl,substituted alkenyl, and —S(O)_(q)R¹³ where q is an integer equal tozero, one or two and R¹³ is selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic, and wherein not more than one—S(O)_(q)R¹³ group is present on the nitrogen-containing ring;

or a prodrug and/or pharmaceutically acceptable salt thereof

In another one of its composition aspects, this invention is directed toa compound of Formula (II):

wherein:

W is a nitrogen-containing ring:

wherein m is 0, 1, 2, or 3; wherein when m is 2, the nitrogen-containingring may optionally contain a double bond between the 4 and 5nitrogen-containing ring positions; wherein when m is 3, thenitrogen-containing ring may optionally contain one double bond betweeneither the 4 and 5 nitrogen-containing ring positions or between the 5and 6 nitrogen-containing ring positions; wherein thenitrogen-containing ring positions are consecutively numberedcounterclockwise beginning with “1” at the nitrogen;

R¹ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, cycloalkylalkyl, halo, alkylsulfanyl, and substitutedalkylsulfanyl;

R²⁰ and R²¹ are independently hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cyano,alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo, or one of R²⁰and R²¹ is ═NOR⁷ and the other is absent, or one of R²⁰ and R²¹ is ═CH₂and the other is absent, or R²⁰ and R²¹ taken together are cycloalkyl,aryl, substituted aryl, heterocyclic, or heteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl,hydroxyalkyl, cycloalkyl, substituted alkyl, iminomethyl, —C(O)O-alkyl,—C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substituted aryl,—C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, -(carboxamido)alkyl,(carbamoyl)alkyl, 5-alkyl-[1,3]dioxol-2-one-4-yl-methyl,5-alkyl-[1,3]dioxol-2-one-4-yl-methoxy-carbonyl, or —N(R⁶)— fragment ispart of the amidine, N-cyanoamidine, N-hydroxyamidine, orN-alkoxyamidine structure;

R⁷ is H or alkyl;

R⁹, which can be singly or multiply substituted in the ring on the sameor different carbons, is independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloalkylalkyl, substituted alkenyl,substituted oxygen, substituted nitrogen, halogen, phenyl, substitutedphenyl, alkylsulfanyl, substituted alkylsulfanyl, substitutedarylsulfanyl, heteroarylsulfanylalkyl, heterocyclicsulfanylalkyl,heteroarylsulfanyl, and heterocyclicsulfanyl, propylidene (═CHCH₂CH₃),azido, —(CH₂)_(n)—OH, —(CH₂)_(n)—NR⁴R⁵, and branched chain isomersthereof wherein n is an integer of from 1 to 8 inclusive and R⁴ and R⁵are H or alkyl, alkoxyalkoxy, aryl, substituted aryl, alkenyl,substituted alkenyl, and —S(O)_(q)R¹³ where q is an integer equal tozero, one or two and R¹³ is selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic, and wherein not more than one—S(O)_(q)R¹³ group is present on the nitrogen-containing ring;

or a prodrug and/or pharmaceutically acceptable salt thereof

In another one of its composition aspects, this invention is directed toa compound of Formula (IA):

wherein:

the

represents a bond that may be a double bond or a single bond;

R¹ is selected from the group consisting of —S-alkyl, —S-substitutedalkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkoxy, substituted alkoxy and halo;

R² and R³ are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl,substituted alkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷and the other is absent, or one of R² and R³ is ═CH₂ and the other isabsent;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, -(carboxamido)alkyl, (carbamoyl)alkyl,

or —N(R⁶)— fragment is part of the amidine, N-cyanoamidine,N-hydroxyamidine, or N-alkoxyamidine structure;

R⁷ is selected from the group consisting of hydrogen and alkyl;

R⁹, which can be singly or multiply substituted in the ring on the sameor different carbons, is independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxyalkoxy,cycloalkyl, substituted cycloalkyl, substituted oxygen, substitutednitrogen, halo, aryl, substituted aryl, alkenyl, substituted alkenyl,and —S(O)_(q)R¹³ where q is an integer equal to zero, one or two and R¹³is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic;

and wherein m¹=0-2;

and wherein t=0-3;

or pharmaceutically acceptable salts and/or prodrugs thereof;

with the following provisos:

A. that in the compounds of formula (I) when

is a single bond,

m¹ is zero or one,

R² and R³ are independently hydrogen, alkyl, hydroxy, fluoro, cyanoalkylor one of R² and R³ is ═NOR⁷ and the other is absent, or one of R² andR³ is ═CH₂ and the other is absent,

R⁶ is hydrogen, alkyl, hydroxyalkyl, —C(O)O-alkylene-cycloalkyl,—C(O)O-alkylene-substituted alkyl, —C(O)O-alkyl, —C(O)O-substitutedalkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-heteroaryl,—C(O)O-substituted heteroaryl, —C(O)O-heterocyclic, —C(O)O-substitutedhetercyclic, —[C(O)O]_(p)-alkylene-heterocycle,—[C(O)O]_(p)-alkylene-substituted heterocycle, where p is zero or one,and

R⁷ is selected from the group consisting of hydrogen and alkyl;

R⁹ is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl,substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo,phenyl, substituted phenyl, —(CH₂)_(n)—OH, —(CH₂)_(n)NR⁴R⁵,-alkylene-R^(a) where R^(a) is selected from monofluorophenyl ormonochlorophenyl, and branched isomers thereof wherein n is an integerfrom 1 to 8 inclusive and R⁴ and R⁵ are hydrogen or alkyl; and

then R¹ is not —S-alkylB. in the compounds of formula (I), when

is a single bond,

R¹ and R³ are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl,substituted alkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷and the other is absent, or one of R² and R³ is ═CH₂ and the other isabsent, with the provisos that both R² and R³ are not hydrogen; when oneof R² and R³ is halo, the other is not hydrogen or hydroxy; and when oneof R² and R³ is hydroxy, the other is not hydrogen or hydroxy;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, -(carboxamido)alkyl, (carbamoyl)alkyl, or —N(R⁶)— fragmentis part of the amidine, N-cyanoamidine, N-hydroxyamidine, orN-alkoxyamidine structure;

R⁷ is selected from the group consisting of hydrogen and alkyl; and

R¹ is selected from the group consisting of —S-alkyl, —S-substitutedalkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkoxy, substituted alkoxy and halo;

then at least one of R⁹ is other than hydrogen, alkyl, substitutedalkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substitutedoxygen, substituted nitrogen, halo, phenyl, substituted phenyl,—(CH₂)_(n)—OH, —(CH₂)_(n)NR⁴R⁵, -alkylene-R^(a) where R^(a) is selectedfrom monofluorophenyl or monochlorophenyl, and branched isomers thereofwherein n is an integer from 1 to 8 inclusive and R⁴ and R⁵ are hydrogenor alkyl,C. in the compounds of formula (I), when

is a single bond,

R² and R³ are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl,substituted alkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷and the other is absent, or one of R² and R³ is ═CH₂ and the other isabsent, with the provisos that both R² and R³ are not hydrogen; when oneof R² and R³ is halo, the other is not hydrogen or hydroxy; and when oneof R² and R³ is hydroxy, the other is not hydrogen or hydroxy;

R⁷ is selected from the group consisting of hydrogen and alkyl; and

R¹ is selected from the group consisting of —S-alkyl, —S-substitutedalkyl, (heteroaryl)alkyl, hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy and halo;

R⁹ is independently selected from other than hydrogen, alkyl,substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl,substituted oxygen, substituted nitrogen, halo, phenyl, substitutedphenyl, —(CH₂)_(n)—OH,

—(CH₂)_(n)NR⁴R⁵, -alkylene-R^(a) where R^(a) is selected frommonofluorophenyl or monochlorophenyl, and branched isomers thereofwherein n is an integer from 1 to 8 inclusive and R⁴ and R⁵ are hydrogenor alkyl,

then R⁶ is selected from the group consisting of substituted alkyl(other than monosubstituted heterocycle or substituted heterocycle),

(carboxamido)alkyl, and an —N(R⁶)— fragment that is part of an amidine,N-cyanoamidine, N-hydroxyamidine, or N-alkoxyamidine structure;

wherein, as used in these provisos only, the following specific termshave the following specific meanings:

substituted alkyl refers to alkyl groups wherein one or more of thehydrogen atoms has been replaced by a halogen, oxygen, hydroxy, amine(primary), amine (secondary-alkyl substituted by alkyl as above), amine(tertiary-alkyl substituted by alkyl as defined above), sulfur, —SH orphenyl),

substituted cycloalkyl refers to cycloalkyl substituted with an alkylgroup, wherein alkyl is as defined above or a group wherein one or moreof the hydrogen atoms has been replaced by a halogen, oxygen, hydroxy,amine (primary), amine (secondary-alkyl substituted by alkyl as above),amine (tertiary-alkyl substituted by alkyl as defined above), sulfur,—SH or phenyl,

substituted oxygen refers to the group —OR^(d) where R^(d) is alkyl,haloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,allkenyl, cycloalkyl, and substituted cycloalkyl,

substituted nitrogen or amino refers to the group —NR^(a)R^(b) whereinR^(a) and R^(b) are independently hydrogen, alkyl, haloalkyl, alkenyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryland substituted heteroaryl,

substituted aryl refers to an aryl ring substituted with one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano, nitro,alkylthio and thioalkyl where alkyl thio refers to the group —S-alkyland thioalkyl refers to an alkyl group having one or more —SH groups,and

substituted heteroaryl refers to a heteroaryl ring substituted with oneor more substituents selected from the group consisting of alkyl,alkenyl, alkynyl, halo, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano,nitro, alkylthio and thioalkyl where alkyl thio refers to the group—S-alkyl and thioalkyl refers to an alkyl group having one or more —SHgroups.

In another one of its composition aspects, this invention is directed toa compound of Formula (IB):

wherein:

R¹ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy,cycloalkylalkyl, halo, and substituted alkylsulfanyl;

R² and R³ are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl,substituted alkylsulfanyl, hydroxy, halo, or one of R² and R³is ═NOR⁷and the other is absent;

R⁶ is H, alkyl, or hydroxyalkyl;

R⁷ is H or alkyl;

R⁹, which can be singly or multiply substituted in the ring on the sameor different carbons, is independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, substituted oxygen, substituted nitrogen,halogen, phenyl, substituted phenyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—NR⁴R⁵,and branched chain isomers thereof wherein n is an integer of from 1 to8 inclusive and R⁴ and R⁵ are H or alkyl; and

m is 1 or 2;

or prodrugs and/or pharmaceutically acceptable salts thereof.

In some embodiments, when the nitrogen-containing ring is saturated,

R² and R³ are independently hydrogen, hydroxyl, halo, alkoxy,alkylsulfanyl, substituted alkylsulfanyl, alkyl, substituted alkyl,hydroxyalkyl

R⁶ is hydrogen, alkyl, hydroxyalkyl;

R⁹ is hydrogen, alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl,substituted phenyl, —(CH₂)_(n)—OH, —(CH₂)_(n)NR⁴R⁵, and branched isomersthereof wherein n is an integer from 1 to 8 inclusive and R⁴ and R⁵ arehydrogen or alkyl; and

then R¹ is not —S-alkyl.

In some embodiments, when the nitrogen containing ring is saturated,

m is 0, 1, 2, or 3,

R² and R³ are independently hydrogen, alkyl, hydroxy, fluoro, cyanoalkylor one of R² and R³ is ═NOR⁷ and the other is absent, or one of R² andR³ is ═CH₂ and the other is absent,

R⁶ is hydrogen, alkyl, hydroxyalkyl, —C(O)O-alkylene-cycloalkyl,—C(O)O-alkylene-substituted alkyl, —C(O)O-alkyl, —C(O)O-substitutedalkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-heteroaryl,—C(O)O-substituted heteroaryl, —C(O)O-heterocyclic, —C(O)O-substitutedhetercyclic, —[C(O)O]_(p)-alkylene-heterocycle,—[C(O)O]_(p)-alkylene-substituted heterocycle, where p is zero or one,and

R⁷ is selected from the group consisting of hydrogen and alkyl;

R⁹ is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl,substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo,phenyl, substituted phenyl, —(CH₂)_(n)—OH, —(CH₂)_(n)NR⁴R⁵,-alkylene-R^(a) where R¹ is selected from monofluorophenyl ormonochlorophenyl, and branched isomers thereof wherein n is an integerfrom 1 to 8 inclusive and R⁴ and R⁵ are hydrogen or alkyl; and

then R¹ is not —S-alkyl.

In some embodiments, when the nitrogen containing ring is saturated,

m is one or two,

R² and R³ are independently hydrogen, alkyl, hydroxy, fluoro, cyanoalkylor one of R² and R³ is ═NOR⁷ and the other is absent, or one of R² andR³ is ═CH₂ and the other is absent,

R⁶ is hydrogen, alkyl, hydroxyalkyl, —C(O)O-alkylene-cycloalkyl,—C(O)O-alkylene-substituted alkyl, —C(O)O-alkyl, —C(O)O-substitutedalkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-heteroaryl,—C(O)O-substituted heteroaryl, —C(O)O-heterocyclic, —C(O)O-substitutedhetercyclic, —[C(O)O]_(p)-alkylene-heterocycle,—[C(O)O]_(p)-alkylene-substituted heterocycle, where p is zero or one,and

R⁷ is selected from the group consisting of hydrogen and alkyl;

R⁹is hydrogen, alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl,substituted cycloalkyl, substituted oxygen, substituted nitrogen, halo,phenyl, substituted phenyl, —(CH₂)_(n)OH, —(CH₂)_(n)NR⁴R⁵,-alkylene-R^(a) where R^(a) is selected from monofluorophenyl ormonochlorophenyl, and branched isomers thereof wherein n is an integerfrom 1 to 8 inclusive and R⁴ and R⁵ are hydrogen or alkyl; and

then R¹ is not —S-alkyl.

In some embodiments, when the nitrogen-containing ring is saturated,

R² and R³ are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl,substituted alkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷and the other is absent, or one of R² and R³is ═CH₂ and the other isabsent, with the provisos that both R² and R³ are not hydrogen; when oneof R² and R³ is halo, the other is not hydrogen or hydroxy; and when oneof R² and R³ is hydroxy, the other is not hydrogen or hydroxy;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, (carboxamido)alkyl, (carbamoyl)alkyl, or —N(R⁶)— fragment ispart of the amidine, N-cyanoamidine, N-hydroxyamidine, orN-alkoxyamidine structure;

R⁷ is selected from the group consisting of hydrogen and alkyl; and

R¹ is selected from the group consisting of —S-alkyl, —S-substitutedalkyl, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkoxy, substituted alkoxy and halo;

then at least one of R⁹ is other than hydrogen, alkyl, substitutedalkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substitutedoxygen, substituted nitrogen, halo, phenyl, substituted phenyl,—(CH₂)_(n)—OH, —(CH₂)_(n)NR⁴R⁵, -alkylene-R^(a) where R^(a) is selectedfrom monofluorophenyl or monochlorophenyl, and branched isomers thereofwherein n is an integer from 1 to 8 inclusive and R⁴ and R⁵ are hydrogenor alkyl,

In some embodiments, when the nitrogen-containing ring is saturated,

R² and R³ are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl,substituted alkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷and the other is absent, or one of R² and R³ is ═CH₂ and the other isabsent, with the provisos that both R² and R³ are not hydrogen; when oneof R² and R³ is halo, the other is not hydrogen or hydroxy; and when oneof R² and R³ is hydroxy, the other is not hydrogen or hydroxy;

R⁷ is selected from the group consisting of hydrogen and alkyl; and

R¹ is selected from the group consisting of —S-alkyl, —S-substitutedalkyl, (heteroaryl)alkyl, hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy and halo;

R⁹ is independently selected from other than hydrogen, alkyl,substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl,substituted oxygen, substituted nitrogen, halo, phenyl, substitutedphenyl, —(CH₂)_(n)—OH,

—(CH₂)_(n)NR⁴R⁵, -alkylene-R^(a) where R^(a) is selected frommonofluorophenyl or monochlorophenyl, and branched isomers thereofwherein n is an integer from 1 to 8 inclusive and R⁴ and R⁵ are hydrogenor alkyl,

then R⁶ is selected from the group consisting of substituted alkyl(other than monosubstituted heterocycle or substituted heterocycle),

(carboxamido)alkyl, and an —N(R⁶)— fragment that is part of an amidine,N-cyanoamidine, N-hydroxyamidine, or N-alkoxyamidine structure.

When used in these provisos above only, the following specific termshave the following specific meanings:

substituted alkyl refers to alkyl groups wherein one or more of thehydrogen atoms has been replaced by a halogen, oxygen, hydroxy, amine(primary), amine (secondary-alkyl substituted by alkyl as above), amine(tertiary-alkyl substituted by alkyl as defined above), sulfur, —SH orphenyl),

substituted cycloalkyl refers to cycloalkyl substituted with an alkylgroup, wherein alkyl is as defined above or a group wherein one or moreof the hydrogen atoms has been replaced by a halogen, oxygen, hydroxy,amine (primary), amine (secondary-alkyl substituted by alkyl as above),amine (tertiary-alkyl substituted by alkyl as defined above), sulfur,—SH or phenyl,

substituted oxygen refers to the group —OR^(d) where R^(d) is alkyl,haloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,allkenyl, cycloalkyl, and substituted cycloalkyl,

substituted nitrogen or amino refers to the group —NR^(a)R^(b) whereinR^(a) and R^(b) are independently hydrogen, alkyl, haloalkyl, alkenyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryland substituted heteroaryl,

substituted aryl refers to an aryl ring substituted with one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano, nitro,alkylthio and thioalkyl where alkyl thio refers to the group —S-alkyland thioalkyl refers to an alkyl group having one or more —SH groups,and

substituted heteroaryl refers to a heteroaryl ring substituted with oneor more substituents selected from the group consisting of alkyl,alkenyl, alkynyl, halo, alkoxy, acyloxy, amino, hydroxy, carboxy, cyano,nitro, alkylthio and thioalkyl where alkyl thio refers to the group—S-alkyl and thioalkyl refers to an alkyl group having one or more —SHgroups.

In some embodiments, both R² and R³ are not hydrogen. In someembodiments, when one of R² and R³ is halo, the other is not hydrogen orhydroxy. In some embodiments, when one of R² and R³ is hydroxy, theother is not hydrogen or hydroxy.

In one embodiment, m is 0

In another embodiment, m is 1

In one embodiment, m is 2. In another embodiment, m is 2, and thenitrogen-containing ring is saturated

In another embodiment, m is 2, and the nitrogen-containing ring containsa double bond between the 4 and 5 nitrogen-containing ring positions

In one embodiment, m is 3. In another embodiment, m is 3, and thenitrogen-containing ring is saturated

In another embodiment, m is 3, and the nitrogen-containing ring containsa double bond between the 4 and 5 nitrogen-containing ring positions

In another embodiment, m is 3, and the nitrogen-containing ring containsa double bond between the 5 and 6 nitrogen-containing ring positions

In one embodiment, the nitrogen-containing ring is saturated.

In a preferred embodiment, this invention provides compounds wherein thenitrogen-containing ring in the Formulas described above is selectedfrom

In one embodiment, R¹ is selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy,substituted alkoxy, halo, alkylsulfanyl, and substituted alkylsulfanyl.In one embodiment, R¹ is selected from the group consisting of hydrogen,alkyl, substituted alkyl, hydroxyalkyl, alkenyl, substituted alkenyl,alkoxy, substituted alkoxy, cycloalkylalkyl, halo, and substitutedalkylsulfanyl. In one embodiment, R¹ is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, hydroxyalkyl, alkoxy,cycloalkylalkyl, alkylsulfanyl, and substituted alkylsulfanyl. In oneembodiment, R¹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, hydroxyalkyl, alkoxy, cycloalkylalkyl, andsubstituted alkylsulfanyl. In a preferred embodiment, R¹ is selectedfrom the group consisting of hydrogen, —S-methyl, —S-iso-propyl,—S-tert-butyl, propyl, 2,2,2-trifluoro-ethyl-sulfanyl,2-ethoxy-eth-1-yl, butoxy, 2-hydroxy-ethyl, 3-hydroxy-propyl,hydroxy-methyl, 2-(methyl-sulfanyl)-ethyl, and cyclopropyl-methyl. Inanother preferred embodiment, R¹ is selected from the group consistingof hydrogen, —S-iso-propyl, —S-tert-butyl, propyl,2,2,2-trifluoro-ethyl-sulfanyl, 2-ethoxy-eth-1-yl, butoxy,2-hydroxy-ethyl, 3-hydroxy-propyl, hydroxy-methyl,2-(methyl-sulfanyl)-ethyl, and cyclopropyl-methyl. In another preferredembodiment, R¹ is —S-methyl. Preferred R¹ groups may be found in TablesI, II and III. In some embodiments, R¹ is not —S-alkyl. In someembodiments, R¹ is not —S-methyl. In other embodiments, R¹ is not—S-substituted alkyl.

In other embodiments, R¹ is preferably —SR⁰ where R⁰ is preferablyC₁₋₄alkyl, and more preferably methyl, 2-hydroxyethyl, or 2-ethylsalicylate. In another embodiment, R¹ is preferably hydrogen, alkyl,substituted alkyl or 2,2,2-trifluoroethylsulfanyl. More preferably, R¹is hydrogen, propyl, 2-ethoxyethyl or 2,2,2-trifluoroethylsulfanyl.

In one embodiment, R² and R³ are independently selected from the groupconsisting of hydrogen, alkyl, hydroxy, and halo. In a preferredembodiment, R² and R³ are independently selected from the groupconsisting of hydrogen, methyl, hydroxy, and chloro. In anotherpreferred embodiment, R² and R³ are hydrogen and hydroxy. In anotherpreferred embodiment, R² and R³ are hydrogen and chloro. In anotherpreferred embodiment, R² and R³ are hydrogen and methyl. Preferred R²and R³ groups may be found in Tables I, II and III.

In one embodiment, R²⁰ and R²¹ are independently alkyl or alkenyl, orR²⁰ and R²¹ taken together are cycloalkyl, aryl, substituted aryl,heterocyclic, or heteroaryl. In one embodiment, one of R²⁰ and R²¹ is Hand the other is alkyl or alkenyl. In a preferred embodiment, one of R²⁰and R²¹ is H and the other is ethyl or ethenyl. In another embodiment,R²⁰ and R²¹ taken together are cycloalkyl or aryl. In a preferredembodiment, R²⁰ and R²¹ taken together are cyclopropyl, cyclopentyl,phenyl, or 4-chloro-phenyl. Preferred R²⁰ and R²¹ groups may be found inTables I, II and III. In one embodiment, when one of R²⁰ and R²¹ ishydrogen, then the other is not hydrogen, alkyl, hydroxy, cyano,alkylsulfanyl, or substituted alkylsulfanyl.

In one embodiment, R⁶ is selected from the group consisting of hydrogen,alkyl, cycloalkyl, hydroxyalkyl, substituted alkyl, iminomethyl,—C(O)O-substituted alkyl, 5-alkyl-[1,3]dioxol-2-one-4-yl-methyl, and5-alkyl-[1,3]dioxol-2-one-4-yl-methoxy-carbonyl. In another embodiment,R⁶ is selected from hydrogen and alkyl. In one embodiment, R⁶ isselected from the group consisting of 1H-imidazol-2-yl-methyl;2-[HC(O)]-eth-1-yl; 2-amino-eth-1-yl; 2-hydroxyethyl;2-methoxy-eth-1-yl; 5-methyl-2-oxo-[1,3]dioxol-4-yl-methoxy-carbonyl;5-methyl-2-oxo-[1,3]dioxol-4-yl-methyl; aminocarbonylmethyl;aminocarbonylethyl; cyanomethyl; cyclopropyl; hydrogen; iminomethyl;methyl; and methoxycarbonylmethyl. In one embodiment, R⁶ is selectedfrom the group consisting of 1H-imidazol-2-yl-methyl; 2-hydroxyethyl;5-methyl-2-oxo-[1,3]dioxol4-yl-methoxy-carbonyl;5-methyl-2-oxo-[1,3]dioxol-4-yl-methyl; aminocarbonylmethyl;cyanomethyl; cyclopropyl; hydrogen; iminomethyl; and methyl. In apreferred embodiment, R⁶ is selected from the group consisting of1H-imidazol-2-yl-methyl; 2-[HC(O)]-eth-1-yl; 2-amino-eth-1-yl;2-hydroxyethyl; 2-methoxy-eth-1-yl; aminocarbonylmethyl;aminocarbonylethyl; cyanomethyl; cyclopropyl; hydrogen; iminomethyl;methyl; and methoxycarbonylmethyl. In a preferred embodiment, R⁶ ishydrogen or methyl. In another preferred embodiment, R⁶ is selected fromthe group consisting of: 5-methyl-[1,3]dioxol-2-one-4-yl-methyl and5-methyl-[1,3]dioxol-2-one-4-yl-methoxy-carbonyl. Preferred R⁶ groupsmay be found in Tables I, II and III.

In another embodiment, R⁹ is selected from the group consisting ofalkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, substitutedalkenyl, alkylsulfanyl, substituted alkylsulfanyl, substitutedarylsulfanyl, heteroarylsulfanylalkyl, heterocyclicsulfanylalkyl,halogen, propylidene (═CHCH₂CH₃), azido, substituted oxygen,heteroarylsulfanyl, and heterocyclicsulfanyl. In another embodiment, R⁹is selected from the group consisting of alkyl, substituted alkyl,cycloalkyl, cycloalkylalkyl, substituted alkenyl, alkylsulfanyl,substituted alkylsulfanyl, substituted arylsulfanyl,heteroarylsulfanylalkyl, heterocyclicsulfanylalkyl, halogen, propylidene(═CHCH₂CH₃), and azido. In a preferred embodiment, R⁹ is alkyl. Inanother preferred embodiment, R⁹ is halogen.

In another embodiment, R⁹ is selected from the group consisting of(2-fluorocyclopropyl)methoxy; (3-fluoropropoxy)methyl;1H-pyrrolylmethyl; 2-(4-ethylthiazol-2-yl)-eth-1-yl;2-(4-methylthiazol-2-yl)-eth-1-yl; 2-(5-ethyl-isoxazol-3-yl)-eth-1-yl;2,2,2-trifluoroethyl-sulfanyl; 2,2-difluoroethoxymethyl;2-[1,3]dithiolan-2-yl-eth-1-yl; 2-chlorophenyl-methylsulfanyl;2-cyclobutylethyl; 2-cyclobutylidene-ethyl; 2-cyclopropylethyl;2-mercaptoethoxy-ethyl-sulfanyl; 2-fluoroethoxy; 2-propoxyethyl;3-(1H-[1,2,3]triazole)-prop-1-yl; 3-(3-fluoropropoxy)propyl;3-(cyclohexyloxy)propyl; 3-(difluoromethylsulfanyl)propyl;3-(ethylthio)propyl; 3-(furan-2-ylmethylsulfanyl)-prop-1-yl;3,3,3-trifluoroprop-1-yl-sulfanyl; 3,3,3-trifluoropropoxy;3,3-difluoroallyl; 3,3-difluorobutyl; 3,3-difluoropropyl;3-[(cyclopropyl)methoxy]propyl; 3-cyanoprop-1-yl; 3-cyclohexyloxypropyl;3-cyclopropyl-propyl; 3-ethoxyiminoprop-1-yl; 3-ethylsulfanylprop-1-yl;3-fluoropropoxy; 3-fluoropropoxymethyl; 3-fluoropropyl;3-imidazol-1-yl-prop-1-yl; 3-mercaptopropylsulfanyl;3-methoxyimino-prop-1-yl; 3-methylbut-1-yl-sulfanyl; 3-methylbutyl;3-pyridin-4-yl-allyl; 3-pyridin-4-yl-propyl;3-pyrrolidin-2-onyl-prop-1-yl; 3-thiophen-2-ylsulfanylprop-1-yl;4-(methoxy)butyl; 4,4-difluorobutyl; 4,4-difluoropentyl; 4-fluorobutoxy;5,5-difluoropentyl; azido; butoxy; butyl; butylsulfanyl; chloro;cyclobutylmethyl; cyclohexylmethyl; cyclopropyl; cyclopropylmethyl;ethyl; ethylsulfanyl; fluoro; isobutyl; methyl; m-methylbenzylsulfanyl;n-butylsulfanyl; o,p-dichlorobenzylsulfanyl; pentoxy; pentyl;p-fluorobenzylsulfanyl; p-fluorophenylsulfanyl; p-methylbenzylsulfanyl;propoxy; propyl; propylidene (═CHCH₂CH₃);p-trifluoromethoxybenzyl-sulfanyl; pyrazin-2-yl-methyl-sulfanyl;pyridin-2-yl-methyl-sulfanyl; pyridin-4-yl-sulfanyl; andthiophen-2-yl-methylsulfanyl.

In another embodiment, R⁹ is selected from the group consisting of2-(4-methylthiazol-2-yl)-eth-1-yl; 2-(5-ethyl-isoxazol-3-yl)-eth-1-yl;2-[1,3]Dithiolan-2-yl-eth-1-yl; 2-cyclobutylethyl;2-cyclobutylidene-ethyl; 2-cyclopropyl-ethyl;3-(difluoromethylsulfanyl)-prop-1-yl;3-(furan-2-ylmethylsulfanyl)-prop-1-yl;3,3,3-trifluoroprop-1-yl-sulfanyl; 3,3-difluoroallyl;3,3-difluoro-propyl; 3-cyanoprop-1-yl; 3-cyclopropyl-propyl;3-ethoxyiminoprop-1-yl; 3-ethylsulfanylprop-1-yl;3-Imidazol-1-yl-prop-1-yl; 3-methoxyimino-prop-1-yl;3-methylbut-1-yl-sulfanyl; 3-methylbutyl; 3-pyridin-4-yl-allyl;3-pyridin-4-yl-propyl; 3-thiophen-2-ylsulfanylprop-1-yl; 4-propyl;azido; butyl; butylsulfanyl; cyclobutylmethyl; cyclopropyl;cyclopropylmethyl; ethyl; ethylsulfanyl; fluoro; methyl;n-butylsulfanyl; o,p-dichlorobenzylsulfanyl; pentyl;p-fluorophenylsulfanyl; p-methylbenzylsulfanyl; propyl; propylidene(═CHCH₂CH₃); pyrazin-2-yl-methyl-sulfanyl; andthiophen-2-yl-methylsulfanyl. In one embodiment, at least one R⁹ groupis other than hydrogen.

In a preferred embodiment, R⁹ is propyl. Preferred R⁹ groups may befound in Tables I, I and III.

In one embodiment, Z is selected from the group consisting of hydrogen,phosphate, and palmitate. In one embodiment, Z is hydrogen. In anotherembodiment, Z is phosphate. In another embodiment, Z is palmitate.

The compounds of this invention also include prodrugs of Formulas (I),(II), (IA), and (IB). Such prodrugs include the compounds of Formulas(I), (II), (IA), and (IB) where R⁶ or one of the hydroxy groups on thesugar are modified to include a substituent selected from phosphate,palmitate or

Preferred prodrugs include the compounds of Formulas (I), (II), (IA),and (IB) where R⁶ or one of the hydroxy groups on the sugar are modifiedto include a substituent selected from

Preferred compounds of formulas (I), (II), (IA), and (IB) have a minimuminhibition concentration of 32 μg/mL or less against at least one of theorganisms selected from the group consisting of Streptococcuspneumoniae, Staphylococcus aureus, Staphylococcus epidermidis,Enterococcus faecalis, Enterococcus faecium, Haemophilus influenzae,Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis,Bacteroides thetaiotaomicron, and Clostridium difficile.

In one embodiment, the compounds of formulas (I), (II), (IA), and (IB)have a minimum inhibition concentration of 4 μg/mL or less against atleast one of the organisms selected from the group consisting ofHaemophilus influenzae and Moraxella catarrhalis. In one embodiment, thecompounds of formulas (I), (II), (IA), and (IB) have a minimuminhibition concentration of 4 μg/mL or less against at least one of theorganisms selected from the group consisting of Enterococcus faecali andEnterococcus faecium. In one embodiment, the compounds of formulas (I),(II), (IA), and (IB) have a minimum inhibition concentration of 4 μg/mLor less against at least one of the organisms selected from the groupconsisting of the Gram negative organisms Haemophilus influenzaeVHIN1003 and Haemophilus influenzae VHIN1004.

In another aspect of the invention are pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound described herein.

In another aspect of the invention are methods for the treatment of amicrobial infection in a mammal comprising administering to the mammal atherapeutically effective amount of a compound described herein. In oneembodiment, the microbial infection being treated is caused by one ormore of the following pathogens: H. influenzae, M catarrhalis, E.faecalis, and E. faecium. The compound administered may be formulatedinto a pharmaceutical composition as described herein. The compound maybe administered to the mammal orally, parenterally, transdermally,topically, rectally, or intranasally in a pharmaceutical composition. Inone embodiment, the compound may be administered in an amount of fromabout 0.1 to about 100 mg/kg body weight/day.

Lincomycin derivatives within the scope of this invention include thoseof Formula I as set forth in Table I as follows, wherein thenitrogen-containing ring positions are consecutively numberedcounterclockwise beginning with “1” at the nitrogen, i.e., TABLE 1

Ex. # R²/R³ R⁶ R⁹ m = R¹ 1 H/Me H 4-(3,3-difluoroallyl) 1 S SMe 2 H/Me H4-(3-pyridin-4-yl-allyl) 1 S SMe 3 H/Me H 4-(3-pyridin-4-yl-propyl) 1 SSMe 4 H/OH H 4-n-butylsulfanyl 1 S SMe 5 H/OH H 4-ethylsulfanyl 1 S SMe6 H/OH H 4-ethylsulfanyl 1 S SMe 7 H/Cl H 4-ethylsulfanyl 1 S SMe 8 H/ClH 4-ethylsulfanyl 1 S SMe 9 H/OH H 4-(p-methylbenzylsulfanyl) 1 S SMe 10H/OH H 4-(p-fluorophenylsulfanyl) 1 S SMe 11 H/OH H4-(3,3,3-trifluoroprop-1-yl-sulfanyl) 1 S SMe 12 H/OH H4-(3-methylbut-1-yl-sulfanyl) 1 S SMe 13 H/OH H4-(o,p-dichlorobenzylsulfanyl) 1 S SMe 14 H/OH H4-(thiophen-2-yl-methylsulfanyl) 1 S SMe 15 H/OH H4-(pyrazin-2-yl-methyl-sulfanyl) 1 S SMe 16 H/Me H4-(o,p-dichlorobenzylsulfanyl) 1 S SMe 17 H/Me H 4-butylsulfanyl 1 S SMe18 H/OH H 4-azido 1 S SMe 19 H/Me H4-[3-(furan-2-ylmethylsulfanyl)-prop-1-yl] 2 S SMe 20 H/Me H4-(3-Imidazol-1-yl-prop-1-yl) 2 S SMe 21 H/Me H4-(3-thiophen-2-ylsulfanylprop-1-yl) 2 S SMe 22 H/Me H4-(3-ethylsulfanylprop-1-yl) 2 S SMe 23 H/Me H 4-(3-cyanopropyl-1-yl) 2S SMe 24 H/Cl H 4-[3-(difluoromethylsulfanyl)-prop-1-yl] 2 S SMe 25 H/MeH 4-[3-(difluoromethylsulfanyl)-prop-1-yl] 2 S SMe 26 H/Me H4-(2-[1,3]Dithiolan-2-yl-eth-1-yl) 2 S SMe 28 H/Me H4-[2-(4-methylthiazol-2-yl)-eth-1-yl] 2 S SMe 29 H/Me H4-(3-methoxyimino-prop-1-yl) 2 S SMe 30 H/Me H4-(3-ethoxyiminoprop-1-yl) 2 S SMe 31 H/Me H4-[2-(5-ethyl-isoxazol-3-yl)-eth-1-yl] 2 S SMe 32 H/Cl H4-propyl/4-fluoro 2 S SMe 33 H/Cl H 4-propyl/4-fluoro 2 S SMe 34 H/OH H4-propyl/4-fluoro 1 S SMe 35 H/Cl H 4-butyl/4-fluoro 1 S SMe 36 H/Cl H4-ethyl/4-fluoro 2 S SMe 37 H/Me H 4-(propylidene) (═CHCH₂CH₃) 2 S SMe38 H/Me H 4-propyl 2 D SMe 39 H/Cl H 4-propyl 2 D SMe 40 H/Meamino-carbonyl-methyl 4-pentyl 1 S SMe 41 H/Me Cyano-methyl 4-pentyl 1 SSMe 42 H/Me 1H-imidazol-2-yl-methyl 4-pentyl 1 S SMe 43 H/Me HN═CH—4-pentyl 1 S SMe 44 H/Me Me 4-propyl 1 S S-iPr 45 H/Me H 4-propyl 2 SS-iPr 46 H/Me Me 4-propyl 1 S S-tBu 47 H/Me H 4-propyl 2 S S-tBu 48 H/Cl5-methyl-[1,3]dioxol-2-one-4-yl-methyl 5-propyl 3 S SMe 49 H/Cl5-methyl-[1,3]dioxol-2-one-4-yl-methoxy- 5-propyl 3 S SMe carbonyl 50H/Cl H 5-methyl 3 S SMe 51 H/Cl H 5-ethyl 3 S SMe 52 H/Cl H5-cyclopropylmethyl 3 S SMe 53 H/Cl H 5-cyclopropyl 3 S SMe 54 H/Cl H4-methyl/5-ethyl 3 S SMe 55 H/Cl H 4-ethyl/5-methyl 3 S SMe 56 H/Cl H5-ethyl/6-methyl 3 S SMe 57 H/Cl H 4-propyl 3 S SMe 58 H/Cl H5-propyl/5-fluoro 3 S SMe 59 H/Cl H 4-propyl 2 D SMe 60 H/Me H 4-butyl 2D SMe 61 H/Cl 2-hydroxyethyl 4-propyl/4-fluoro 2 S SMe 62 H/Cl H4-butyl/4-fluoro 2 S SMe 63 H/Cl H 4-(2-cyclobutylethyl) 2 S SMe 64 H/ClH 4-(cyclopropylmethyl) 1 S SMe 65 H/Cl H 4-(cyclopropylmethyl) 2 S SMe66 H/Me H 4-(2-cyclobutylidene-ethyl) 1 S SMe 67 H/Cl H4-(2-cyclobutylidene-ethyl) 1 S SMe 68 H/Cl H 4-(2-cyclobutyl-ethyl) 1 SSMe 69 H/Cl H 4-(cyclobutylmethyl) 2 S SMe 70 H/Cl H 5-propyl 3 D SMe 4,5 71 H/Cl H 4-(2-cyclopropyl-ethyl) 1 S SMe 72 H/Cl H4-cyclopropylmethyl/4-fluoro 2 S SMe 73 H/Cl H 5-propyl 3 S SMe 74 H/ClH 5-propyl 3 S SMe 75 H/Me Cyclopropyl 5-propyl 3 S SMe 76 H/Cl H4-butyl 2 D SMe 77 H/Me H 5-propyl 3 S S-iPr 78 H/Me H 5-propyl 3 SS-tBu 80 H/Cl H 3-cyclopropylmethyl 0 S SMe 81 H/Cl H3-(2-cyclobutylethyl) 0 S SMe 82 H/Cl H 3-(2-cyclopropylethyl) 0 S SMe83 H/Cl H 3-(3-cyclopropyl-propyl) 0 S SMe 84 H/Cl H 3-propyl 0 S SMe 85H/Cl H 3-butyl 0 S SMe 86 H/Cl 2-hydroxy-ethyl 3-butyl 0 S SMe 87 H/Cl H3-pentyl 0 S SMe 88 H/Cl H 3-(3-methylbutyl) 0 S SMe 89 H/Cl H3-(3,3-difluoro-propyl) 0 S SMe 90 H/Cl Me 3-butyl 0 S SMe — H/Me H(2-fluorocyclopropyl)methoxy 2 S SMe — H/OH H4-(p-trifluoromethoxybenzyl-sulfanyl 1 S SMe — H/Cl H2-(3-fluoropropoxy)methyl/fluoro 2 S SMe — H/Cl H2-(propoxy)ethyl/fluoro 2 S SMe — H/Cl H 2,2-difluoroethoxymethyl 2 SSMe — H/Cl H 2,2-difluoroethoxymethyl/fluoro 2 S SMe — H/Cl H2-fluoroethoxy 2 D SMe — H/Cl H 2-fluoroethoxy/fluoro 2 S SMe — H/Cl H3-(3-fluoropropoxy)propyl/fluoro 2 S SMe — H/Cl H3-(cyclohexyloxy)propyl 2 D SMe — H/Cl H 3-(cyclohexyloxy)propyl/fluoro2 S SMe — H/Me H 3-(difluoromethylsulfanyl)propyl 2 S SMe — H/Cl H3-(ethylthio)propyl/fluoro 2 S SMe — H/Cl H 3,3,3-trifluoropropoxy 2 SSMe — H/Cl H 3,3,3-trifluoropropoxy/fluoro 2 S SMe — H/Cl H3,3-difluorobutyl/fluoro 2 S SMe — H/Cl H 3,3-difluoropropyl 2 D SMe —H/Cl H 3,3-difluoropropyl/fluoro 2 S SMe — H/Cl H3-[(cyclopropyl)methoxy]propyl 2 D SMe — H/Cl H3-[(cyclopropyl)methoxy]propyl/Fluoro 2 S SMe — H/Cl H 3-fluoropropoxy 2D SMe — H/Cl H 3-fluoropropoxy/fluoro 2 S SMe — H/Cl H3-fluoropropyl/fluoro 2 S SMe — H/Me H 4-(1H-Pyrrolylmethyl) 2 S SMe —H/OH H 4-(2,2,2-trifluoroethyl-sulfanyl) 1 S SMe — H/OH H4-(2-chlorophenyl-methylsulfanyl) 1 S SMe — H/OH H4-[2-(2-mercapto-ethoxy)-ethylsulfanyl] 1 S SMe — H/Me H4-(3-cyclohexyloxypropyl) 2 S SMe — H/OH H 4-(3-mercaptopropylsulfanyl)1 S SMe — H/Me H 4-(3-pyrrolidin-2-onyl-prop-1-yl) 2 S SMe — H/Cl H4-(methoxy)butyl/fluoro 2 S SMe — H/OH H 4-(m-methylbenzylsulfanyl) 1 SSMe — H/OH H 4-(p-fluorobenzylsulfanyl) 1 S SMe — H/OH H4-(pyridin-2-yl-methyl-sulfanyl) 1 S SMe — H/OH H4-(pyridin-4-yl-sulfanyl) 1 S SMe — H/Cl H 4,4-difluorobutyl 2 D SMe —H/Cl H 4,4-difluorobutyl/fluoro 2 S SMe — H/Cl H 4,4-difluoropentyl 2 DSMe — H/Cl H 4,4-difluoropentyl/fluoro 2 S SMe — H/Me H4-[2-(4-ethylthiazol-2-yl)-eth-1-yl] 2 S SMe — H/Me H4-{3-(1H-[1,2,3]triazole)-prop-1-yl} 2 S SMe — H/Cl H 4-fluorobutoxy 2 SSMe — H/Cl H 4-fluorobutoxy/fluoro 2 S SMe — H/Me Amino-carbonyl-ethyl4-pentyl 1 S SMe — H/Me 2-methoxy-eth-1-yl 4-pentyl 1 S SMe — H/Me2-[HC(O)]-eth-1-yl 4-pentyl 1 S SMe — H/Me 2-amino-eth-1-yl 4-pentyl 1 SSMe — H/Me Methoxy carbonyl methyl 4-pentyl 1 S SMe — H/Cl H5,5-difluoropentyl 2 D SMe — H/Cl H 5,5-difluoropentyl/fluoro 2 S SMe —H/Cl H Butoxy 2 D SMe — H/Cl H butoxy/fluoro 2 S SMe — H/Cl H Butyl 2 DSMe — H/Cl H butyl/fluoro 2 S SMe — H/Cl H Cyclohexylmethyl 2 D SMe —H/Cl H cyclohexylmethyl/fluoro 2 S SMe — H/Cl H Ethyl 2 D SMe — H/Cl HIsobutyl 2 D SMe — H/Cl H isobutyl/fluoro 2 S SMe — H/Cl Hpentoxy/fluoro 2 S SMe — H/Cl H Pentyl 2 D SMe — H/Cl HN═CH—pentyl/fluoro 1 S SMe — H/Cl H Propoxy 2 D SMe — H/Cl H Propoxy/fluoro 2S SMe — H/Cl HN═CH— Propyl 2 S SMe — H/Cl HN═CH— Propyl 2 D SMe — H/Cl Hpropyl/chloro 2 S SMe — H/Cl Me propyl/chloro 2 S SMe — H/Cl Mepropyl/fluoro 2 S SMe — H/Cl HN═CH— propyl/fluoro 2 S SMe — H/Me H2-(3-fluoropropoxy)methyl 2 S SMe — H/Me H 2-(propoxy)ethyl 2 S SMe —H/Me H 2,2-difluoroethoxymethyl/fluoro 2 S SMe — H/Me H 2-fluoroethoxy 2S SMe — H/Me H 3-(3-fluoropropoxy)propyl 2 S SMe — H/Me H3,3,3-trifluoropropoxy 2 S SMe — H/Me H 3,3-difluoropropyl/fluoro 2 SSMe — H/Me H 3-[(cyclopropyl)methoxy]propyl 2 S SMe — H/Me H3-fluoropropoxy 2 S SMe — H/Me H 3-fluoropropyl/fluoro 2 S SMe — H/Me H4-(methoxy)butyl 2 S SMe — H/Me H 4,4-difluoropentyl 2 S SMe — H/Me H4-fluorobutoxy 2 S SMe — H/Me 9H-fluoren-9-yl-methoxy carbonyl 4-propyl2 S SMe — H/Me Ethoxy carbonyl 4-propyl 2 S SMe — H/Mephenyloxy-carbonyl 4-propyl 2 S SMe — H/Me5-methyl-2-oxo-[1,3](dioxol-4-ylmethyl 4-propyl 2 S SMe — H/Me5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxy carbonyl 4-propyl 2 S SMe — H/MeH 4-propyl/4-fluoro 2 S SMe — H/Me H 4-propyl/4-fluoro 1 S SMe — H/Me Hbutyl/fluoro 2 S SMe — H/Me H ethyl/fluoro 2 S SMe 107 H/Me H 4-Pentyl 1S Propyl 108 H/Me H 4-Propyl 2 S Propyl 109 H/Me H 4-Propyl 2 S2,2,2-Trifluoro-Ethyl-sulfanyl 110 H/Me H 4-Pentyl 1 S 2-Ethoxy-eth-1-yl111 H/Me 2-Hydroxy-ethyl 4-Pentyl 1 S Propyl 112 H/Me H 4-Pentyl 1 S H113 H/Me H 4-pentyl 1 S Butoxy 114 H/Me Me 4-butyl 1 S propyl 119 H/Me5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl 4-pentyl 1 S propyl 120 H/Me5-methyl-2-oxo-[1,3]dioxol-4-yl-methoxy- 4-pentyl 1 S Propyl carbonyl121 H/Me 5-methyl-2-oxo-[1,3]dioxol-4-yl-methyl 4-propyl 1 S Propyl 122H/Me 5-methyl-2-oxo-[1,3]dioxol-4-yl-methoxy- 4-propyl 1 S Propylcarbonyl 123 H/Me H 4-propyl 1 S 2-hydroxy-ethyl 124 H/Me H 4-propyl 1 S3-hydroxy-propyl 125 H/Me H 4-propyl 1 S Hydroxyl-methyl 126 H/Me H4-propyl 1 S 2-(Methyl-sulfanyl)-ethyl 127 H/Me H 4-propyl 1 SCyclo-propyl-methylIn Table I, unless otherwise noted, the R⁹ substituents are substitutedat the 4-position, when m is 0 or 1.

In Table I, unless otherwise noted, the R⁹ substituents are substitutedat the 4-position, when m is 0 or 1.

Additional lincomycin derivatives within the scope of this inventioninclude those of formula II as set forth in Table II as follows, whereinthe nitrogen-containing ring positions are numbered as in Formula (I).TABLE 1I Ex. # R²⁰/R²¹ R⁶ R⁹ m ═ R¹ 91 R²⁰/R²¹ = cyclopropyl Me 4-propyl1 S SMe 92 R²⁰/R²¹ = Cyclopropyl H 4-propyl 2 S SMe 93 R²⁰/R²¹ =Cyclopropyl H 5-propyl 3 S SMe 94 R²⁰/R²¹ = phenyl H 4-propyl 2 S SMe 95R²⁰/R²¹ = phenyl Me 4-propyl 1 S SMe 96 R²⁰/R²¹ = Cyclopentyl H 4-propyl2 S SMe 97 R²⁰/R²¹ = Cyclopentyl Me 4-propyl 1 S SMe 98 R²⁰/R²¹ =Cyclopentyl H 5-propyl 3 S SMe 99 H/ethyl H 5-propyl 3 S SMe 100H/ethenyl Me 4-propyl 1 S SMe 101 H/ethenyl H 4-propyl 2 S SMe 102H/ethyl H 4-propyl 2 S SMe 103 R²⁰/R²¹ = 4-Chloro-phenyl Me 4-propyl 1 SSMe 104 R²⁰/R²¹ = 4-Chloro-phenyl H 4-propyl 2 S SMe 105 H/ethyl Me4-propyl 1 S SMe 106 R²⁰R²¹ = 4-chloro-phenyl H 5-propyl 3 S SMe

Additional lincomycin derivatives within the scope of this inventioninclude those of formula II as set forth in Table III as follows:

wherein the nitrogen-containing ring positions are numbered as inFormula (I). TABLE III Ex No. R¹ Z R²/R³ R⁶ R⁹ m 115 Propyl —P(═O)(OH)₂H/Me H 4-pentyl 1 116 Propyl —C(O)(CH₂)₁₄—CH₃ H/Me H 4-pentyl 1 117Propyl —P(═O)(OH)₂ H/Me H 4-propyl 1 118 Propyl —C(O)(CH₂)₁₄—CH₃ H/Me H4-propyl 1

In Tables I, II, and III above, the following abbreviations are used:

-   -   S=single bond    -   D=double bond D 4,5=double bond between 4 and 5        nitrogen-containing ring positions    -   Me=methyl    -   Pr=propyl    -   Bu=butyl    -   i=iso-    -   t=tert-

As used below, these compounds are named based on amine derivatives but,alternatively, these compounds could have been named based on1-thio-L-threo-α-D-galacto-octopyranoside derivatives.

Preferred compounds within the scope of this invention include thefollowing compounds:

-   4-(3,3-Difluoro-allyl)-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Pyridin-4-yl-allyl)-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Pyridin-4-yl-propyl)-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Butylsulfanyl-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(4-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(4-Fluoro-phenylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3,3,3-Trifluoro-propylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Methyl-butylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(Thiophen-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(Pyrazin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Butylsulfanyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Azido-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-[3-(Furan-2-ylmethylsulfanyl)-prop-1-yl]-piperidine-2-carboxylic    acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Imidazol-1-yl-prop-1-yl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-[3-(Thiophen-2-ylsulfanyl)-prop-1-yl]-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Ethylsulfanyl-prop-1-yl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Cyano-prop-1-yl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Difluoromethylsulfanyl-prop-1-yl)-piperidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Methoxyimino-prop-1-yl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Ethoxyimino-prop-1-yl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-[2-(5-Ethyl-isoxazol-3-yl)-ethyl]-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-4-propyl-piperidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-4-butyl-pyrrolidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-4-ethyl-piperidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Propylidene-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-Cyanomethyl4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-(1H-Imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Propyl-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid    [1-(6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;-   4-Propyl-piperidine-2-carboxylic acid    [1-(6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;-   1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-5-propyl-azepane-2-carboxylic    acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   2-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-propyl-azepane-1-carboxylic    acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;-   5-Methyl-azepane-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   5-Ethyl-azepane-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   5-Cyclopropylmethyl-azepane-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   5-Cyclopropyl-azepane-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   5-Ethyl-4-methyl-azepane-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Ethyl-5-methyl-azepane-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   5-Ethyl-6-methyl-azepane-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Propyl-azepane-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   5-Fluoro-5-propyl-azepane-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Butyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-1-(2-hydroxy-ethyl)-4-propyl-pyrrolidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-=methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Butyl-4-fluoro-piperidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(2-Cyclobutyl-ethyl)-piperidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Cyclopropylmethyl-pyrrolidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Cyclopropylmethyl-piperidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(2-Cyclobutylidene-ethyl)-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(2-Cyclobutylidene-ethyl)-pyrrolidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(2-Cyclobutyl-ethyl)-pyrrolidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Cyclobutylmethyl-piperidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   5-Propyl-2,3,6,7-tetrahydro-1H-azepine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(2-Cyclopropyl-ethyl)-pyrrolidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Cyclopropylmethyl-4-fluoro-piperidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   5-Propyl-azepane-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-Cyclopropyl-5-propyl-azepane-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Butyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   5-Propyl-azepane-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   5-Propyl-azepane-2-carboxylic acid    [1-(6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;-   3-Cyclopropylmethyl-azetidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   3-(2-Cyclobutyl-ethyl)-azetidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   3-(2-Cyclopropyl-ethyl)-azetidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   3-(3-Cyclopropyl-propyl)-azetidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   3-Propyl-azetidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   3-Butyl-azetidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   3-Butyl-1-(2-hydroxy-ethyl)-azetidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   3-Pentyl-azetidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   3-(3-Methyl-butyl)-azetidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   3-(3,3-Difluoro-propyl)-azetidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   3-Butyl-1-methyl-azetidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid    [cyclopropyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide;-   4-Propyl-piperidine-2-carboxylic acid    [cyclopropyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide;-   5-Propyl-azepane-2-carboxylic acid    [cyclopropyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide;-   4-Propyl-piperidine-2-carboxylic acid    [phenyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide;-   1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid    [phenyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide;-   4-Propyl-piperidine-2-carboxylic acid    [cyclopentyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide;-   1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid    [cyclopentyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide;-   5-Propyl-azepane-2-carboxylic acid    [cyclopentyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide;-   5-Propyl-azepane-2-carboxylic acid    [1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-butyl]-amide;-   1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid    [1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-but-3-enyl]-amide;-   4-Propyl-piperidine-2-carboxylic acid    [1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-but-3-enyl]-amide;-   4-Propyl-piperidine-2-carboxylic acid    [1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-butyl]-amide;-   1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid    [(4-chloro-phenyl)-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide;-   4-Propyl-piperidine-2-carboxylic acid    [(4-chloro-phenyl)-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide;-   1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid    [1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-butyl]-amide;-   5-Propyl-azepane-2-carboxylic acid    [(4-chloro-phenyl)-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide;-   4-Pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Propyl-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Propyl-piperidine-2-carboxylic acid    {2-methyl-1-[3,4,5-trihydroxy-6-(2,2,2-trifluoro-ethylsulfanyl)-tetrahydro-pyran-2-yl]-propyl}-amide;-   4-Pentyl-pyrrolidine-2-carboxylic acid    [1-(6-ethoxyethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;-   1-(2-Hydroxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Pentyl-pyrrolidine-2-carboxylic acid    [1-(6-butoxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;-   4-Butyl-1-methyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   Phosphoric acid    mono-(4,5-dihydroxy-6-{2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl)-amino]-propyl}2-propyl-tetrahydro-pyran-3-yl)    ester;-   Hexadecanoic acid    4,5-dihydroxy-6-{2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl)-amino]-propyl}-2-propyl-tetrahydro-pyran-3-yl    ester;-   Phosphoric acid    mono-(4,5-dihydroxy-6-{2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl)-amino]-propyl}2-propyl-tetrahydro-pyran-3-yl)    ester;-   Hexadecanoic acid    4,5-dihydroxy-6-{2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl)-amino]-propyl}-2-propyl-tetrahydro-pyran-3-yl    ester;-   1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic    acid    [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   2-[2-Methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidine-1-carboxylic    acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;-   1-(5-Methyl-2-oxo-[1,3]dioxol4-ylmethyl)-4-propyl-pyrrolidine-2-carboxylic    acid    [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   2-[2-Methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-pyrrolidine-1-carboxylic    acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;-   4-Propyl-pyrrolidine-2-carboxylic acid    {2-methyl-1-[3,4,5-trihydroxy-6-(2-hydroxy-ethyl)-tetrahydro-pyran-2-yl]-propyl}-amide;-   4-Propyl-pyrrolidine-2-carboxylic acid    {2-methyl-1-[3,4,5-trihydroxy-6-(3-hydroxy-propyl)-tetrahydro-pyran-2-yl]-propyl}-amide;-   4-Propyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Propyl-pyrrolidine-2-carboxylic acid    {2-methyl-1-[3,4,5-trihydroxy-6-(2-methylsulfanyl-ethyl)-tetrahydro-pyran-2-yl]-propyl}-amide;-   4-Propyl-pyrrolidine-2-carboxylic acid    [1-(6-cyclopropylmethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;-   or a prodrug and/or a pharmaceutically acceptable salt thereof.

Additional compounds within the scope of this invention include:

-   4-(Thiophen-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(4-Fluoro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(4-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(Pyridin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(Pyrazin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid    [2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Butylsulfanyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3,3-Difluoro-allyl)-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Pyridin-4-yl-allyl)-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Pyridin-4-yl-propyl)-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-(2-Methoxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-(1H-Imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-(2-Formylamino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-(2-Amino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Cyclohexyloxy-propyl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   {2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidin-1-yl}-acetic    acid methyl ester;-   1-Methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-[3-(Furan-2-ylmethylsulfanyl)-propyl]-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-imidazol-1-yl-propyl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-[3-(Thiophen-2-ylsulfanyl)-propyl]-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Methoxyimino-propyl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-[2-(4-Ethyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Ethylsulfanyl-propyl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Ethoxyimino-propyl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Pyrrol-1-ylmethyl-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic    acid 9H-fluoren-9-ylmethyl ester;-   2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic    acid ethyl ester;-   4-(3-Cyano-propyl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic    acid phenyl ester;-   2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylic    acid phenyl ester;-   4-(2-[1,2,3]Triazol-1-yl-ethyl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Propylidene-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylic    acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-4-propyl-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-4-propyl-piperidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid    [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   4-Pentyl-pyrrolidine-2-carboxylic acid    [1-(6-ethoxymethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;-   or a prodrug and/or a pharmaceutically acceptable salt thereof.

Additional compounds of the invention include:

-   phosphoric acid    mono-(6-{2-chloro-1-[(5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl)    ester;-   phosphoric acid    mono-(6-{2-chloro-1-[(5-fluoro-5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl)    ester;-   phosphoric acid    mono-(6-{2-chloro-1-[(5-cyclopropylmethyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl)    ester;-   phosphoric acid    mono-(6-{2-chloro-1-[(4-fluoro-4-propyl-piperidine-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl)    ester;-   hexadecanoic acid    6-{2-chloro-1-[(5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl    ester;-   hexadecanoic acid    6-{2-chloro-1-[(5-fluoro-5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl    ester;-   hexadecanoic acid    6-{2-chloro-1-[(5-cyclopropylmethyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl    ester; and-   hexadecanoic acid    6-{2-chloro-1-[(4-fluoro-4-propyl-piperidine-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl    ester.

Additional compounds of the invention include:

-   2-[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-propyl-azepane-1-carboxylic    acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester-   2-[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-fluoro-5-propyl-azepane-1-carboxylic    acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;-   5-fluoro-1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-5-propyl-azepane-2-carboxylic    acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   5-cyclopropylmethyl-1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-azepane-2-carboxylic    acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;-   2-[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-cyclopropylmethyl-azepane-1-carboxylic    acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;-   2-[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-fluoro-4-propyl-piperidine-1-carboxylic    acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester; and-   4-fluoro-1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylic    acid    [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.

The compounds, prodrugs and pharmaceutically acceptable salts thereof,as defined herein, may have activity against bacteria, protozoa, fungi,and/or parasites.

In another aspect, this invention provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of the compounds defined herein. The pharmaceuticalcompositions of the present invention may further comprise one or moreadditional antibacterial agents. In one embodiment, one or more of theadditional antibacterial agents may be active against gram negativebacteria. In one embodiment, one or more of the additional antibacterialagents may be active against gram positive bacteria. In anotherembodiment, at least one of the antibacterial agents may be activeagainst both gram negative and gram positive bacteria.

In one of its method aspects, this invention is directed to a method forthe treatment of a microbial infection in a mammal comprisingadministering to the mammal a therapeutically effective amount of acompound of this invention. The compound of this invention may beadministered to the mammal orally, parenterally, transdermally,topically, rectally, or intranasally in a pharmaceutical composition.

In another of its method aspects, this invention is directed to a methodfor the treatment of a microbial infection in a mammal comprisingadministering to the mammal a pharmaceutical composition comprising atherapeutically effective amount of a compound of this invention. Thepharmaceutical compositions of the present invention may furthercomprise one or more additional antibacterial agents. In one embodiment,one or more of the additional antibacterial agents may be active againstgram negative bacteria. In one embodiment, one or more of the additionalantibacterial agents may be active against gram positive bacteria. Thepharmaceutical composition may be administered to the mammal orally,parenterally, transdermally, topically, rectally, or intranasally.

In a preferred embodiment, the microbial infection being treated is agram positive infection. In another embodiment, the infection may be agram negative infection. In a further embodiment, the infection may be amycobacteria infection, a mycoplasma infection, or a chlamydiainfection.

In yet another aspect, the present invention provides novelintermediates and processes for preparing the compounds describedherein.

DETAILED DESCRIPTION OF THE INVENTION

As described above, this invention relates to lincomycin derivativesthat exhibit antibacterial activity, in particular gram positiveantibacterial activity. In some embodiments, said novel lincomycinderivatives exhibit antibacterial activity against gram positive andanaerobe pathogens. Surprisingly, selected novel lincomycin compoundsdescribed herein exhibit atypical potency against Enterocci species suchas Enterocci faecium and Enterocci faecalis, and/or against fastidiousgram-negative pathogens such as Haemophilus influenzae, when comparedagainst known compounds such as clindamycin. However, prior todescribing this invention in further detail, the following terms willfirst be defined.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural references unlesscontext clearly dictates otherwise. Thus, for example, a reference to “apharmaceutically acceptable carrier” includes a plurality of suchcarriers; a reference to “an additional antibacterial agent” is areference to one or more agents and to equivalents thereof known tothose skilled in the art, and so forth.

Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the meanings given below:

“Acyl” means the group —C(O)R¹⁴ wherein R¹⁴ is hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic orsubstituted heterocyclic.

“Acylamino” refers to —NR^(a)C(O)R¹⁴ where R^(a) and R¹⁴ are as definedabove.

“Alkenyl” means a linear unsaturated monovalent hydrocarbon radical oftwo to eight carbon atoms or a branched monovalent hydrocarbon radicalof three to eight carbon atoms containing at least one double bond,(—C═C—) and preferably from 1-2 double bonds. Examples of alkenyl groupsinclude, but are not limited to, allyl, vinyl, 2-butenyl, and the like.

“Alkoxy” refers to the group “alkyl-O—” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto eight carbon atoms or a branched saturated monovalent hydrocarbonradical of three to eight carbon atoms. Examples of alkyl groupsinclude, but are not limited to, groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, and thelike.

“Alkylene” means a linear divalent hydrocarbon group of one to eightcarbon atoms or a branched divalent hydrocarbon group of three to eightcarbon atoms. Examples of alkylene groups include, but are not limitedto, methylene, ethylene, 2-methylpropylene, and the like.

“Alkylsulfanyl” refers to the group “alkyl-S—” wherein alkyl is asdefined herein which includes, by way of example, methylsulfanyl,butylsulfanyl, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to eightcarbon atoms or a branched monovalent hydrocarbon radical of three toeight carbon atoms containing at least one triple bond, (—C≡C—), andpreferably a single triple bond. Examples of alkynyl groups include, butare not limited to, ethynyl, propynyl, 2-butynyl, and the like.

“Amino” or “substituted nitrogen” refers to the group “—NR^(a)R^(b)”wherein R^(a) and R^(b) are independently hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic or where R^(a) and R^(b) aretethered together with the nitrogen atom to which they are bound to forma heterocyclic ring.

“Aminoacyl” refers to —C(O)NR^(a)R^(b).

“Aminocarbonylalkyl” means a group “—R^(c)C(O)NR^(a)R^(b)” where R^(c)is an alkylene and R^(a) and R^(b) are as defined above.

“Aryl” means a monovalent monocyclic or bicyclic aromatic carbocyclicgroup of 6 to 14 ring atoms. Examples include, but are not limited to,phenyl, naphthyl, and anthryl. The aryl ring may be optionally fused toa 5-, 6-, or 7-membered monocyclic non-aromatic ring optionallycontaining 1 or 2 heteroatoms independently selected from oxygen,nitrogen, or sulfur, the remaining ring atoms being C where one or two Catoms are optionally replaced by a carbonyl. Representative aryl groupswith fused rings include, but are not limited to,2,5-dihydro-benzo[b]oxepine, 2,3-dihydrobenzo[1,4]dioxane, chroman,isochroman, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran,benzo[1,3]dioxole, 1,2,3,4-tetrahydroisoquinoline,1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1Hindole,2,3-dihydro1H-isoindole, benzimidazole-2-one, 2-H-benzoxazol-2-one, andthe like.

“Carboxy” means the group “C(O)OH.”

“Cyanoalkyl” refers to an alkyl substituted with one or more cyano (—CN)groups provided that no more than a single cyano group is present on thesame carbon atom. Examples of cyanoalkyl groups include, for example,cyanomethyl, 2-cyanoethyl, 2-cyanopropyl, and the like.

“Cycloalkyl” means a cyclic saturated hydrocarbon group of 3 to 8 ringatoms. Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

“Cycloalkylalkyl” means a group —R^(c)R^(d) where R^(c) is an alkylenegroup and R^(d) is a cycloalkyl group, as defined above. Examplesinclude, but are not limited to, cyclopropylmethylene,cyclohexylethylene, and the like.

“Halo” or “Halogen” means fluoro, chloro, bromo, or iodo.

“Haloalkyl” means an alkyl substituted with one or more, preferably oneto 6, of the same or different halo atoms. Examples of haloalkyl groupsinclude, for example, trifluoromethyl, 3-fluoropropyl,2,2-dichloroethyl, and the like.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms containing one, two, or three ring heteroatomsselected from N, O, or S, the remaining ring atoms being C.

“Heterocycle” or “heterocyclic” refers to a saturated or unsaturatedgroup having a single ring or multiple condensed rings, from 1 to 10carbon atoms and from 1 to 4 hetero atoms selected from the groupconsisting of nitrogen, oxygen or S(O)_(q) (where q is zero, one or two)within the ring wherein, in fused ring systems, one or more of the ringscan be aryl or heteroaryl.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydro-isoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and thelike.

“Hydroxy” means the group —OH.

“Hydroxyalkyl” refers to an alkyl substituted with one or more —OHgroups provided that no more, than a single hydroxy (—OH) group ispresent on the same carbon atom. Examples of hydroxyalkyl groupsinclude, for example, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl,and the like.

“Mammal” refers to all mammals including humans, livestock, andcompanion animals.

“Optional” or “optionally” means that the subsequently described eventor circumstance may, but need not, occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “aryl group optionally mono- ordi-substituted with an alkyl group” means that the alkyl may but neednot be present, and the description includes situations where the arylgroup is mono- or disubstituted with an alkyl group and situations wherethe aryl group is not substituted with the alkyl group.

“Pharmaceutically acceptable carrier” means a carrier that is useful inpreparing a pharmaceutical composition that is generally safe, non-toxicand neither biologically nor otherwise undesirable, and includes acarrier that is acceptable for veterinary use as well as humanpharmaceutical use. “A pharmaceutically acceptable carrier” as used inthe specification and claims includes both one and more than one suchcarrier.

“Pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

(1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; or

(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth metal ion, or an aluminum ion; or coordinates with anorganic base such as ethanolamine, diethanolamine, triethanolamine,N-methylglucamine, and the like.

“Pro-drugs” mean any compound which releases an active parent drugaccording to a compound of the subject invention in vivo when suchprodrug is administered to a mammalian subject. Prodrugs of a compoundof the subject invention are prepared by modifying functional groupspresent in a compound of the subject invention in such a way that themodifications may be cleaved in vivo to release the parent compound.Prodrugs include compounds of the subject invention wherein a hydroxy,sulfhydryl or amino group in the compound is bonded to any group thatmay be cleaved in vivo to regenerate the free hydroxy, sulfhydryl, oramino group, respectively. Examples of prodrugs include, but are notlimited to, esters (e.g., acetate, formate, palmitate, and benzoatederivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyfunctional groups in compounds of the subject invention, and the like.Preferred prodrug substituents include the following substituentsattached to the N-position of the five or six member nitrogen containingheterocycle: phosphate, palmitate or

“Substituted alkyl” means an alkyl group, as defined above having 1-3independently selected substitutents selected from the group consistingof cyano, a halogen (i.e., Cl, Br, F, or I), acyl, substituted oxygen,hydroxy, alkylsulfanyl, substituted alkylsulfanyl, cycloalkyl,substituted cycloalkyl, aminocarbonylalkyl, carboxy, —C(O)H, —C(O)OR¹⁵(where R¹⁵ is alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl and the like), —C(O)NR^(a)R^(b), substitutednitrogen, ═N—OR⁷ where R⁷ is hydrogen or alkyl, —SH, —S(O)_(q)R¹⁶ [whereq is zero, one or two, and R¹⁶ is alkyl, haloalkyl, aryl, heteroaryl,heterocyclic and alkyl substituted with aryl, heteroaryl, cycloalkyl andheterocyclic], aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic. Examples ofsubstituted alkyl groups include, but are not limited to, 1-fluoroethyl,1-chloroethyl, 2-fluoroethyl, 2-chloroethyl, 1-bromopropyl,2-iodopropyl, 1-chlorobutyl, 4-flurobutyl, 4-chlorobutyl,2-ethoxyeth-1-yl, —CH₂—S(O)₂CH₃, and the like.

“Substituted alkenyl” means an alkenyl group, as defined above, in whichone or more of the hydrogen atoms, and preferably 1 to 3 hydrogen atoms,has been replaced by substituents as defined for substituted alkyl.

“Substituted alkynyl” means an alkynyl group, as defined above, in whichone or more of the hydrogen atoms, and preferably 1 to 3 hydrogen atoms,has been replaced by substituents as defined for substituted alkyl.

“Substituted alkylsulfanyl” refers to the group —S-substituted alkylwhere substituted alkyl is as defined above, which includes, by way ofexample, 2-hydroxyethylsulfanyl, and the like.

“Substituted alkoxy” refers to the group —O-substituted alkyl wheresubstituted alkyl is as defined above.

“Substituted aryl” means an aryl ring substituted with one or moresubstituents, preferably one to three substituents selected from thegroup consisting of alkyl, substituted alkyl, alkylsulfanyl, substitutedalkylsulfanyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, halo, alkoxy, substituted alkoxy, acyl, amino, acylamino,acylamino, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, hydroxy, carboxy, —C(O)OR¹⁵, —C(O)NR^(a)R^(b), cyano,nitro and sulfanylalkyl. The aryl ring may be optionally fused to a 5-,6-, or 7-membered monocyclic non-aromatic ring optionally containing 1or 2 heteroatoms independently selected from oxygen, nitrogen, orsulfur, the remaining ring atoms being C where one or two C atoms areoptionally replaced by a carbonyl.

“Substituted cycloalkyl” means a cycloalkyl substituted with an alkylgroup or a group as defined above for substituted alkyl. Representativeexamples include, but are not limited to, 2-cyclopropylethyl,3-cyclobutylpropyl, 4-cyclopentylbutyl, 4-cyclohexylbutyl, and the like.

“Substituted heteroaryl” means a heteroaryl ring substituted with one ormore substituents, preferably one to three substituents selected fromthe group defined above for substituted aryl.

“Substituted heterocyclic” refers to heterocycle groups that areindependently substituted with from 1 to 3 of the same substituents asdefined for substituted cycloalkyl.

“Substituted oxygen” refers to the group “—O—R^(d)” wherein R^(d) isalkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic or substituted heterocyclic.

“Substituted phenyl” refers to phenyl groups having from 1 to 3substituents selected from the group defined for substituted aryl.

“Sulfanylalkyl” refers to an alkyl substituted with one or more —SHgroups provided that if two thiol groups are present they are not bothon the same carbon atom. Examples of sulfanylalkyl groups include, forexample, sulfanylmethyl, 2-sulfanylethyl, 2-sulfanylpropyl, and thelike.

“Therapeutically effective amount” means the amount of a compound that,when administered to a mammal for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and itsseverity and the age, weight, etc., of the mammal to be treated.

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of thedisease not to develop in a mammal that may be exposed to or predisposedto the disease but does not yet experience or display symptoms of thedisease,

(2) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms, or

(3) relieving the disease, i.e., causing regression of the disease orits clinical symptoms.

The compounds of the present invention are generally named according tothe IUPAC or CAS nomenclature system. Abbreviations that are well knownto one of ordinary skill in the art may be used (e.g. “Ph” for phenyl,“Me” for methyl, “Et” for ethyl, “h” for hour or hours and “rt” for roomtemperature).

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs.

Before the present compositions and methods are described, it is to beunderstood that the invention is not limited to the particularmethodologies, protocols, assays, and reagents described, as these mayvary. It is also to be understood that the terminology used herein isintended to describe particular embodiments of the present invention,and is in no way intended to limit the scope of the present invention asset forth in the appended claims.

Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of the presentinvention, the preferred methods, devices, and materials are nowdescribed. All publications cited herein are incorporated herein byreference in their entirety for the purpose of describing and disclosingthe methodologies, reagents, and tools reported in the publications thatmight be used in connection with the invention. Nothing herein is to beconstrued as an admission that the invention is not entitled to antedatesuch disclosure by virtue of prior invention.

The practice of the present invention will employ, unless otherwiseindicated, conventional methods of chemistry, biochemistry, molecularbiology, cell biology, and pharmacology, within the skill of the art.Such techniques are explained fully in the literature.

General Synthetic Schemes

Compounds of this invention can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Toranto ResearchChemicals (North York, ON Canada), Aldrich Chemical Co. (Milwaukee,Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemie, or Sigma (St.Louis, Mo., USA) or are prepared by methods known to those skilled inthe art following procedures set forth in references such as Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley andSons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989), Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition), and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989). Theseschemes are merely illustrative of some methods by which the compoundsof this invention can be synthesized, and various modifications to theseschemes can be made and will be suggested to one skilled in the arthaving referred to this disclosure.

As it will be apparent to those skilled in the art, conventionalprotecting groups may be necessary to prevent certain functional groupsfrom undergoing undesired reactions. Suitable protecting groups forvarious functional groups, as well as suitable conditions for protectingand deprotecting particular function groups are well known in the art.For example, numerous protecting groups are described in T. W. Greeneand G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition,Wiley, New York, 1991, and references cited therein.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

The compounds of this invention will typically contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers. All such stereoisomers (and enrichedmixtures) are included within the scope of this invention, unlessotherwise indicated. Pure stereoisomers (or enriched mixtures) may beprepared using, for example, optically active starting materials orstereoselective reagents well-known in the art. Alternatively, racemicmixtures of such compounds can be separated using, for example, chiralcolumn chromatography, chiral resolving agents, and the like.

Preparation of Compounds of the Invention

In general, to prepare the compounds of formula (I) of the presentinvention, an appropriately 7-substititued lincosamine intermediate andan appropriately substituted pyrrolidinyl, piperidyl, azetindinyl, orazepane carboxylic acid are condensed under reactive conditions,preferably in an inert organic solvent, in the presence of a couplingreagent and an organic base. This reaction can be performed with anynumber of known coupling reagents, such asO-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HATU), 1-hydroxybenzotriazole hydrate (HOBT) withcarbodiimides, isobutyl chloroformate, and the like. Suitable organicbases include diisopropylethylamine (DIEA), triethylamine (TEA),pyridine, N-methyl morpholine, and the like. Suitable inert organicsolvents which can be used include, for example, N,N-dimethylformamide,acetonitrile, dichloromethane, and the like. This reaction is typicallyconducted using an excess of carboxytic acid to lincosamine attemperatures in the range of about 0° C. to about 50° C. The reaction iscontinued until completion, which typically occurs in from about 2 to 12hours.

Appropriately 7-substititued lincosamine intermediates, as defined inthe present invention (i.e., R²/R³), are synthesized by methods wellknown to those of skill in the art from methyl6-amino-6,8-dideoxy-1-thio-erythro-α-D-galacto-octopyranoside, which canbe prepared as described by Hoeksema, H. et. al. Journal of the AmericanChemical Society, 1967, 89 2448-2452. Illustrative syntheses for7-substituted lincosamine intermediates are shown below in Schemes 1-6.

Additional appropriately 7-substititued lincosamine intermediates, asdefined in the present invention (i.e., R²/R³), are synthesized bymethods well known to those of skill in the art from methyl6-amino-6,8-dideoxy-1-thio-erythro-α-D-galacto-octopyranoside asdisclosed in U.S. Pat. No. 3,086,912 (R2=OH, R3=H), U.S. Pat. No.3,496,136, U.S. Pat. No. 3,502,646 or preferably European Pat. No.0161794 (R2=Halogen, R3=H), U.S. Pat. No. 3,179,565 (R2=SR, R3=H), U.S.Pat. No. 3,544,551 (R2=SH, R3=H).

Appropriately substituted pyrrolidinyl or piperidyl carboxylic acidintermediates, as defined in the present invention (i.e., R⁹), are alsosynthesized by methods well known to those of skill in the art fromprolines and pyridines. The prolines and pyridines that can be used inthe synthesis of the carboxylic acid intermediates of the presentinvention include, for example, 4-oxoproline and 4-substitutedpyridines. The prolines and pyridines used in the synthesis arecommercially available from vendors such as Aldrich and Sigma.Alternatively, these prolines and pyridines can be prepared by methodswell known in the art. Illustrative syntheses for appropriatelysubstituted pyrrolidinyl or piperidyl carboxylic acid intermediates areshown below in Schemes 7-12.

Scheme 1 below illustrates a general synthesis of a lincosamineinternediate 1c wherein P is an N-protecting group, preferably eitherCbz or Boc, and R¹ is as defined for formula (I).

As shown in Scheme 1, methyl6-amino-6,8-dideoxy-1-thio-erythro-α-D-galacto-octopyranoside 1a isprepared as described by Hoeksema, H. et. al. Journal of the AmericanChemical Society, 1967, 89, 2448-2452. The amino functional group andthe hydroxy functional groups of the product 1a are then protected withsuitable protecting groups. Suitable N-protecting groups (P) can beformed by the addition of di-t-butyldicarbonate,N-(benzyloxycarbonyloxy) succinimide, and the like. The hydroxy groupscan be protected as silyl ethers. The hydroxy group can be converted totrimethylsilyl (TMS) ethers by reaction withN,O-bis-(trimethylsilyl)-trifluoroacetamide in the presence of anappropriate organic base such as triethylamine or trimethylsilylchloride in the presence of an organic base such as triethylamine. TheN-protection is typically accomplished before the O-protection.Chromatography of the crude product on silica after evaporation of thesolvent provides the protected product 1b.

The 7-O-trimethylsilyl group of 1b is chemoselectively deprotected andoxidized to provide the 7-keto-lincosamine derivative 1c. This selectivetransformation is performed by addition of the protected product 1b todimethylsulfoxide and oxalyl chloride in an inert organic solvent suchas dichloromethane followed by an appropriate organic base such astriethylamine. Alternatively, the transformation may be performed byaddition of 1b to dimethyl sulfoxide and an appropriate activating agentsuch as trifluoroacetic anhydride in an inert organic solvent. Thereaction is typically conducted at temperatures in the range ofapproximately −70° C. The resulting reaction mixture is stirred at thelow temperature and is then allowed to warm to approximately −50° C. Thereaction is maintained at this second temperature for approximately 1 hto 3 h. To the reaction mixture is added a suitable organic base, suchas TEA, pyridine, and the like. The reaction mixture is appropriatelyworked up to provide the product 1c. The general class of conditionsused in the transformation of 1b to 1c is known in the art as Swernoxidation conditions.

Scheme 2 below illustrates a general synthesis of a lincosamineintermediate 2b wherein P is an N-protecting group, preferably eitherCbz or Boc, R³ is hydrogen, R^(2′) is consistent with R² as defined forformula (I), and R¹ is as defined for formula (I).

As shown in Scheme 2, a keto-lincosamine intermediate 1c is reacted toform an alkene using the Wittig or Homer-Wadsworth-Emmons reaction. Inthis reaction, a suitable phosphonium salt or phosphonate isdeprotonated using a strong base to form a phosphorus ylide. Suitablephosphonium salts which can be used are alkyltriphenylphosphoniumhalides, which can be prepared by the reaction of triphenylphosphine andan alkyl halide. Suitable phosphorous compounds include, for example,methyltriphenylphosphonium bromide, diethyl(cyanomethyl)phosphonate andthe like. Suitable strong bases which can be used to form the ylideinclude organolithium reagents, potassium tert-butoxide, and the like.The formation of the phosphorus ylide is typically conducted under aninert atmosphere, such as N₂, in an inert organic solvent such astoluene, THF, or the like, at low temperatures.

After formation of the phosphorus ylide, the product 1c is added to thereaction. The reaction conveniently can be performed at temperaturesbetween −40° C. and room temperature and is stirred until completion,typically 1 to 4 hours. The resulting organic solution is worked-up andchromatography of the crude product on silica provides the alkeneproduct 2a.

The product 2a is then hydrogenated to provide the saturated product 2b.The hydrogenation is typically performed in a polar organic solvent suchas methanol, ethanol, and the like, using 10% Palladium on carbon in aParr bottle. The bottle is purged, and charged with H₂ to approximately50 to 70 psi and shaken until completion, typically approximately 12 to24 h. The resulting reaction mixture is filtered, e.g., through celite,and rinsed with a polar organic solvent such as methanol. The organicsolution is worked up by transferring to a resin fimnel containing dry,washed Dowex 50w-400x H⁺ form and shaken. After washing the resin withmethanol and water, the product 2b is eluted from the resin by washingwith 5% TEA in MeOH. The product can also be purified by silica gelcolumn chromatography.

Scheme 3 illustrates a general synthesis of a lincosamine intermediate3b wherein P is an N-protecting group, preferably either Cbz or Boc, oneof R² or R³ is alkyl and the other is —OH, and R¹ is as defined forformula (I).

As shown in Scheme 3, suitable carbon nucleophiles are added to7-ketolincosamine intermediate 1c in suitable inert organic solvents toprovide 7-hydroxy lincosamine intermediate 3b. Suitable carbonnucleophiles include methylmagnesium chloride, diethyl zinc, sodiumacetylide, and the like, and suitable inert organic solvents which canbe used include THF, diethyl ether, toluene, and the like. The reactionis typically conducted at reduced temperatures, approximately at 0° C.,for about 3 to 5 h. The reaction is then quenched with a saturatedaqueous acidic solution, such as saturated aqueous NH₄Cl/H₂O. Thequenched mixture is then worked up and can be purified by chromatographyto provide the product 3b.

Scheme 4 below illustrates a general synthesis of a lincosamineintermediate 4b wherein P is a N-protecting group, preferably Boc, R¹ isas defined for formula (I), and R²/R³ is an oxime (═NOR⁷), wherein R⁷ isas defined for formula (I).

As shown in Scheme 4, the lincosamine intermediate 1c is converted tothe oxime by stirring in the presence of a suitable reagent such asO-trimethylsilylhydroxylamine, O-alkylhydroxylamine hydrochloride (forexample, O-methylhydroxylamine hydrochloride), and the like. Thereaction is typically conducted in a polar organic solvent such asmethanol. The reaction conveniently can be conducted at rt inapproximately 8 to 24 h. The solvent is removed to provide theN-protected product 4a.

Removal of the protecting group can be carried out with acids, such astriflouoroacetic acid (TFA), hydrochloric acid, p-toluenesulfonic acid,and the like, in an inert organic solvent such as dichloromethane,dichloroethane, dioxane, THF, and the like. The removal is typicallyconducted at low temperatures, e.g., 0° C., and then gradually allowedto warn to room temperature to provide the product 4b.

Scheme 5 below illustrates a general synthesis of a lincosamineintermediate 5b wherein R² and R³ are both fluorine, P is anN-protecting group, preferably Cbz or Boc, and R¹ is as defined forformula (I).

As shown in Scheme 5, the lincosamine intermediate 1c is contacted witha suitable fluoride in an inert organic solvent. Suitable fluorideswhich can be used include tetrabutylammonium fluoride, Amberlite resinA-26 F⁻ form, HF•pyridine and the like. Suitable inert organic solventsinclude THF, acetonitrile, dichloromethane, dioxane, and the like. Thereaction conveniently can be conducted at rt in about 1 to 2 h. Theproduct (not shown) can be purified on a silica gel column.

The O-protecting groups on the product obtained from the column areconverted by contact with acetic anhydride and dimethylaminopyridine(DMAP) in a suitable mixture of an inert organic solvent and an organicbase, such as, for example, dichloromethane and pyridine. The reactionconveniently can be conducted at rt in approximately 6 to 12 hours. Theproduct can be purified on silica gel column to provide product 5a.

The product 5a is contacted with a suitable fluorinating reagent andthen the N-protecting group is removed to provide the product 5b.Suitable fluorinating reagents which can be used include, for example,dimethylaminosulfurtrifluoride,[bis(2-methoxyethyl)-amino]sulfurtrifluoride, and the like. The reactionis typically conducted in an inert organic solvent such asdichloromethane, ethylacetate, THF, and the like at room temperature inapproximately 6 to 12 h.

Removal of the protecting group can be carried out with acids, such astriflouoroacetic acid (TFA), hydrochloric acid, p-toluenesulfonic acid,and the like, in an inert organic solvent such as dichloromethane,dichloroethane, dioxane, THF, and the like. The removal is typicallyconducted at low temperatures, e.g., 0° C., and then gradually allowedto warm to room temperature to provide the product 5b.

Scheme 6 below illustrates a general synthesis of a lincosamineintermediate 6b wherein P is a N-protecting group, preferablytrifluoroacyl, one of R² and R³ is hydrogen and the other is Cl, Br orI, and R¹ is as defined for formula (I).

As shown in Scheme 6, lincosamine intermediate 1a is N-protected with asuitable trifluoroacylating reagent in the presence of base in asuitable organic solvent. Suitable trifluoroacylating reagents includemethyltrifluoroacetate, ethyl trifluorothioacetate, trifluoroaceticanhydride and the like. Suitable organic solvents include methanol, THF,acetonitrile, dichloromethane, dioxane, and the like. The reactionconveniently can be conducted at ambient temperature in about 2 to 4 h.Protected lincosamide intermediate 6a may be purified by crystallizationor used crude in the subsequent reactions.

Halogenation of the 7-position of protected intermediate 6a isaccomplished by contact with a suitable Rydon reagent as described byMagerlein, B. J.; Kagen, F. Journal of Medicinal Chemistry, 1969, 12,780-784 or an amidehalide salt as disclosed in European Pat. No.0161794. Suitable Rydon reagents include triphenylphosphene dichloride,triphenylphosphene dibromide and the like in an inert organic solventsuch as acetonitrile, dichloromethane, dichloroethane, or toluene.Suitable haloamide salt reagents include1-N-(Chloromethylene)-piperidine chloride1-N-(Chloromethylene)-N-methylmethaninium chloride and the like in inertorganic solvents such as acetonitrile, dichloromethane, dichloroethane,or toluene. The reaction is typically conducted at temperatures rangingfrom approximately 24° C. to 70° C., for 16 to 24 h with an excess ofhalogenating reagent. Hydrolysis of the halogenated product adducts (notshown) and removal of the protecting group in aqueous base provides7-deoxy-7-halolincosamide intermediate 6b. Suitable bases are NaOH, KOHand concentrated ammonia in water or admixtures of water with miscibleorganic solvent such as methanol, acetonitrile, tetrahydrofuran, dioxaneand the like. The reaction is typically conducted under conditions thatprecipitate the crude 7-deoxy-7-halolincosamide intermediate 6b.7-deoxy-7-halolincosamide intermediate 6b may be purified bycrystallization from an appropriate solvent or solvent system.

Alternately 1c may be directly halogenated as disclosed in U.S. Pat. No.3,496,136 or U.S. Pat. No. 3,502,646 by contact with a suitable Rydonreagent or amidehalide salt as disclosed in European Pat. No. 0161794.Hydrolysis of the halogenated product adduct (not shown) in aqueous baseprovides 7-deoxy-7-halolincosamide intermediate 6b.

Scheme 7 below illustrates a general synthesis of trans R^(9″)-prolineintermediates 7d, wherein R^(9″) is alkyl or substituted alkyl.

As shown in Scheme 7, a protected 5-oxoproline 7a is enolated with asuitable base and then alkylated with a suitable alkylating agent in aninert organic solvent to provide a lactam 7b (wherein R^(9′) isalkenyl), as described in the literature procedure by Zhang, R.; et. al.Journal of the American Chemical Society, 1998, 120, 3894-3902. Compound7a is commercially available from vendors such as Bachem. Alternatively,7a can be prepared by methods well known in the art. Suitable basicenolating agents include LiHMDS, LiN(ipr)₂, and the like, and suitablealkylating agents include allylic and benzylic bromides, for example,4-bromo-2-methyl-2-butene and cis-1-bromo-2-pentene, allylbromide, andthe like.

The lactam 7b is reduced using a suitable reducing agent to provide apyrrolidine 7c, wherein R^(9′) is alkenyl. The reduction is preformed bya two-step sequence involving Superhydride® reduction of the lactam tothe hemiaminal and the subsequent reduction of the hemiaminal. Suitablereducing agents that can be used include Et₃SiH/BF₃.OEt₂, Et₃SiH/TiCl₄,and the like.

The pyrrolidine 7c is then hydrogenated to simultaneously remove theunsaturation in the R^(9′) substitutent and remove the benzyl protectinggroup from the carboxylic acid to provide the product 7d. Thehydrogenation is typically performed in a polar organic solvent such asmethanol, ethanol, and the like, using 10% Palladium on carbon in a Parrbottle. The bottle is purged, and charged with H₂ to approximately 50 to70 psi and shaken until completion, typically approximately 5 to 24 h.The reaction mixture is filtered, e.g., through a celite pad, and washedwith a polar organic solvent, such as methanol. Evaporation of thecombined washings and filtrate affords the product 7d, wherein R^(9″) isan alkyl or substituted alkyl.

Scheme 8 below illustrates a general synthesis of trans-R⁹-prolineintermediates 8b and 8c, wherein R^(9′) is alkenyl or substitutedalkenyl and R^(9″) is alkyl or substituted alkyl.

As shown in Scheme 8, the product 7c is ozonized to provide the aldehydewhich is then treated under Wittig conditions to provide 8a. Theozonolysis reaction is typically conducted in an anhydrous inert organicsolvent, such as dichloromethane, dioxane, THF, and the like, at lowtemperatures, e.g., −78° C., followed by quenching of the reaction witha reducing agent such as DMS, Ph₃P.

The aldehyde is reacted with a suitable phosphonium salt in the presenceof a strong base in an inert organic solvent. Suitable phosphonium saltswhich can be used include, for example, fluorobenzyl phosphoniumchloride, 4-chlorobenzyl phosphonium chloride, dibromofluoromethane andtriphenylphosphine, and the like. Suitable bases which can be usedinclude potassium t-butoxide, organolithium reagents, and activatedzinc. Suitable organic solvents which can be used include toluene, THF,dimethylacetamide, and the like. The reaction is typically conducted inan inert atmosphere, such as under nitrogen, with vigorous stirring. Thereaction is typically conducted at rt to approximately 110° C. for 1 to2 h. The resulting reaction mixture is appropriately worked-up and canbe purified by chromatography to provide 8b.

The intermediate 8b is then hydrogenated to provide the product 8c. Thehydrogenation is typically performed in a polar organic solvent such asmethanol, ethanol, and the like, using 10% Palladium on carbon in a Parrbottle. The bottle is purged, and charged with H₂ to approximately 40 to70 psi and shaken until completion, typically approximately 4 to 24 h.The reaction mixture is filtered, e.g., through a celite pad and washedseveral times with a polar organic solvent, such as methanol.Evaporation of the combined washings and filtrate affords the product8c, wherein R^(9″) is an alkyl or substituted alkyl and corresponds tothe saturated form of product 8b.

Alternately, intermediate 8b may be saponified by methods well known tothose of skill in the art by contact with aqueous alkali and a miscibleorganic co-solvent to provide R^(9′) unsaturated amino acid intermediate8c.

Scheme 9 below illustrates a general synthesis of a proline intermediate9d wherein R⁹ is as defined for formula (I).

Scheme 10 below illustrates a general synthesis, as described in Shuman,R. T.; Journal of Organic Chemistry. 1990, 55, 741-750, of substitutedpyridine carboxylic acid intermediates 10b, wherein R⁹ is as defined forformula (I).

As shown in Scheme 10, an appropriately substituted pyridine iscontacted with a suitable oxidizing agent in an inert organic solvent.The appropriately substituted pyridine starting materials arecommercially available from vendors such as Aldrich and Sigma.Alternatively, these pyridines can be prepared by methods well known inthe art. Suitable oxidizing agents that can be used include hydrogenperoxide, MCPBA, and the like. The reaction is typically conducted atreflux for 6 to 12 h. The reaction mixture is then contacted with asuitable cyanide reagent to provide the cyano-substituted pyridine 10a.Suitable cyanide reagents that can be used include trimethylsilylcyanide, HCN, and the like. Suitable inert organic solvents includedichloromethane, dioxane, THF, and the like. The reaction convenientlycan be conducted at rt in approximately 6 to 12 h. The reaction mixtureis worked up to provide the cyano-substituted pyridine 10a.

The cyano-substituted pyridine 10a is then hydrolyzed to provide thepyridin-2-yl carboxylic acid 10b by contact with a suitable acid.Suitable acids for hydrolyzing the cyano group to the carboxylic acidinclude hydrochloric acid, aqueous sulfuric acid, and the like. Thereaction is typically conducted at reflux in 6 to 12 h.

Scheme 11 below illustrates a general synthesis of pyridine andpiperidine intermediates, wherein R⁹ is as defined for formula (I).

Scheme 12 below illustrates a general synthesis of a prolineintermediate 12d wherein R⁹ is as defined for formula (I).

As shown in Scheme 12, the ketoproline 12a is allylated to form ahydroxy allyl proline, whose hydroxy functionality is subsequentlyreplaced by fluorine. Hydrogenation of the allyl double bond providesthe fluoro alkyl proline 12c, which is deprotected to form 12d.

Scheme 13 below illustrates the coupling reaction of a lincosamineintermediate, prepared as described above in Schemes 1-6, and apyrrolidinyl or piperidyl carboxylic acid, prepared as described abovein Schemes 7-12, wherein R¹, R², R³, R⁶, and R⁹ are as defined forformula (1) and P¹ is a suitable O-protecting group and P² is a suitableN-protecting group.

As shown in Scheme 13, an appropriately 7-substititued lincosamineintermediate (prepared, for example, according to any one of Schemes1-6) and an appropriately substituted pyrrolidinyl or piperidylcarboxylic acid (prepared, for example, according to any one of Schemes7-9 or 11-12) are condensed under reactive conditions, preferably in aninert organic solvent, in the presence of a coupling reagent and anorganic base. This reaction can be performed with any number of knowncoupling reagents, such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), 1-hydroxybenzotriazole hydrate (HOBT) withcarbodiimides, isobutylchloroformate, and the like. Suitable organicbases include diisopropylethylamine (DIEA), triethylamine (TEA),pyridine, N-methyl morpholine, and the like. Suitable inert organicsolvents which can be used include, for example, N,N-dimethylformamide,acetonitrile, dichloromethane, and the like. This reaction is typicallyconducted using an excess of carboxylic acid to lincosamine attemperatures in the range of about 0° C. to about 50° C. The reaction iscontinued until completion, which typically occurs in from about 2 to 12hours.

Removal of the protecting groups can be carried out with acids, such astrifluoroacetic acid (TFA), hydrochloric acid, p-toluenesulfonic acid,and the like, in an inert organic solvent such as dichloromethane,dichloroethane, dioxane, THF, and the like. The removal is typicallyconducted at low temperatures, e.g., 0° C., and then gradually allowedto warm to room temperature to provide the product.

Also as shown in Scheme 13, an appropriately 7-substititued lincosamineintermediate (prepared, for example, according to any one of Schemes1-6) and an appropriately substituted pyridin-2-yl carboxylic acid(prepared, for example, according to Scheme 10) are condensed underreactive conditions, preferably in an inert organic solvent, in thepresence of a coupling reagent and an organic base, as described above.

The pyridine 13b is hydrogenated to provide the piperidyl product. Thehydrogenation is typically performed in a polar organic solvent such asmethanol, ethanol, and the like, using Platinum (IV) oxide in thepresence of an acid such as HCl, acetic acid, and the like, in a Parrbottle. The bottle is purged, and charged with H₂ to approximately 40 to70 psi and shaken until completion, typically approximately 24 h. Thereaction mixture is filtered, e.g. through a celite pad, and washedseveral times with a polar organic solvent such as methanol. Evaporationof the combined washings and filtrate affords the piperidyl product.

The coupling of pyridine carboxylic acids and lincosamines to providepyridine 13b followed by reduction to the piperidyl product may also beconducted as described in Birkenmeyer, R. D; et al; Journal of MedicinalChemistry 1984, 27, 216-223.

Scheme 14 below illustrates the coupling reaction of a lincosanineintermediate, prepared as described above in Schemes 1-6, and apyrrolidinyl or piperidyl carboxylic acid, prepared as described abovein Schemes 7-12, wherein R¹, R², R³, and R⁹ are as defined for formula(I) and P is a suitable N-protecting group. The coupling reactionsdescribed herein may also be used to coupling azetidinyl and azepanecarboxylic acids.

Scheme 15 illustrates general synthetic methods for building protected1-allylic intermediates 15b, 15c, 15e, 15f. where R², R³, R⁹ are asdefined for formula (I) and P₁ and P₂ indicate suitable N- andO-protecting groups, respectively.

In scheme 15, P₁ and P₂ are preferentially differentially removableprotecting groups. Displacement of the methylsulfanyl (methylsulfanyl)group by a fluoro substituent is accomplished by contact with DAST inthe presence of N-bromosuccinimide (NBS) and in suitable solvent such asdichloromethane (DCM) which provides for compounds 15b and 15e.

In turn, the fluoro group is displaced to form the allyl substituent bycontact with trimethylallylsilane in the presence of the trifluoroboratediethyl ether complex. Subsequent removal of the Boc (t-butoxycarbonyl)protecting group with trifluoroacetic acid (TFA) provides for thedeprotected product. Alternatively, conventional defluorination of the1-des(methylsulfanyl)-1-fluoro-2,3,4-tri-O-benzyl-7-deoxy-7-methyllincosamineleads to the1-des(methylsulfanyl)-2,3,4-tri-O-benzyl-7-deoxy-7-methyllincosamine(i.e., R¹ is hydrogen).

Conventional amide coupling of the carboxyl group ofN-Boc-4-pentyl-proline with1-des(methylsulfanyl)-1-allyl-2,3,4-tri-O-benzyl-7-deoxy-7-methyllincosamine,in the presence of a coupling promoter such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in dimethylformamide (DMF) and triethylamine(TEA) leads to compounds 15c and 15f. The allyl group of compounds 15cand 15f provides a ready source for numerous modifications at the1-position of the lincosamine group.

Scheme 16 illustrates general synthetic methods for building, wherein R¹is alkylsulfanyl, substituted alkylsulfanyl, R², R³, R⁹ are as definedfor formula (I) and P₁ and P₂ indicate suitable N- and O-protectinggroups, respectively.

Scheme 16 illustrates that nucleophilic displacement of the 1-fluorogroup by a suitable sulfanyl moiety can be accomplished either on thelincosame moiety to form compound 16a or on the coupled lincosaminederivative to form compound 16b. The nucleophilic displacement occursusing conventional techniques well known in the art.

Scheme 17 illustrates general synthetic methods for building alcohol andether substituents at the 1-position, wherein R², R³, R⁹ are as definedfor formula (I), P₁ and P₂ indicate suitable N- and O-protecting groups,respectively, and R is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, or substituted heteroaryl.

Scheme 17 illustrates that the 1-(dessulfanylmethyl)-1-allyl-lincosaminederivative can be oxidized to the corresponding aldehyde which isreduced to the primary alcohol by conventional methods such asozonolysis followed by reduction with sodium borohydride preferably in aprotic solvent such as methanol. Subsequently, the primary alcohol iscontacted with an appropriate base such as sodium hydride and a suitablealkyl halide to form the ether derivative as either the lincosamineentity or as the coupled lincosamine derivative to provide for compounds17c and 17f respectively.

Scheme 18 illustrates deprotection schemes for 15f, 16b, and 17f,wherein R², R³, R⁹ are as defined for formula (I), P is a suitableN-protecting groups, and R¹ is consistent with schemes 15, 16, and 17,respectively.

Scheme 18 illustrates that conventional deprotection leads to compoundsof formula (I).

Scheme 19 below illustrates the alkylation of nitrogen of thepyrrolidinyl or piperidyl ring, wherein R⁶ is alkyl or hydroxyalkyl andR¹, R², R³, and R⁹ are as defined for formula (I).

As shown in Scheme 19, the lincosamine 18a can be N-substituted bycontact with an alkylating agent in the presence of a suitable base toprovide a product 18b. Suitable alkylating agents that can be usedinclude epoxides, alkyl bromides, and the like. Suitable bases that canbe used include potassium carbonate, cesium carbonate triethylamine, andthe like. The alkylation reaction is typically conducted in a polarorganic solvent such as methanol or DMF. The alkylation reaction istypically conducted at low temperatures in the range of 0° C. to −10° C.for 10 to 20 h.

In Scheme 20, R², R³, R⁶ and R⁹ are as defined for formula (I), P₂ is asuitable O-protecting group.

Scheme 21 below illustrates a versatile synthetic sequence allowing thesynthesis of unsaturated N-protected amino acids 21k ring, wherein m andR⁹ are as defined for formula (I).

As shown in Scheme 21, suitable N-allylic amino esters 21f may beappended with pseudoephedrine which serves as a chiral auxiliary,allowing stereospecific alkylation of the carbon with a suitable allylicbromide 21d. Protection of the secondary amine followed by olefinmetathesis and cleavage of the chiral auxiliary leads to 4,5 unsaturatedN-protected cyclic amino acids 21k.

Pharmaceutical Formulations

When employed as pharmaceuticals, the compounds of the subject inventionare usually administered in the form of pharmaceutical compositions.These compounds can be administered by a variety of routes includingoral, parenteral, transdermal, intravenous, intramuscular, topical,rectal, and intranasal. These compounds are effective as both injectableand oral compositions. Such compositions are prepared in a manner wellknown in the pharmaceutical art and comprise at least one activecompound.

This invention also includes pharmaceutical compositions that contain,as the active ingredient, one or more of the compounds of the subjectinvention above associated with one or more pharmaceutically acceptablecarriers. In making the compositions of this invention, the activeingredient is usually mixed with an excipient, diluted by an excipientor enclosed within such a carrier which can be in the form of a capsule,sachet, paper or other container. The excipient employed is typically anexcipient suitable for administration to human subjects or othermammals. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The quantity of active component, which is the compound according to thesubject invention, in the pharmaceutical composition and unit dosageform thereof may be varied or adjusted widely depending upon theparticular application, the potency of the particular compound and thedesired concentration.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 5 to about 100 mg, more usually about 10 toabout 30 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient. Preferably, the compound of the subject invention above isemployed at no more than about 20 weight percent of the pharmaceuticalcomposition, more preferably no more than about 15 weight percent, withthe balance being pharmaceutically inert carrier(s).

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically or therapeuticallyeffective amount. It will be understood, however, that the amount of thecompound actually administered will be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the severity of the bacterial infection being treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

In therapeutic use for treating, or combating, bacterial infections inwarm-blooded animals, the compounds or pharmaceutical compositionsthereof will be administered orally, topically, transdermally, and/orparenterally at a dosage to obtain and maintain a concentration, thatis, an amount, or blood-level of active component in the animalundergoing treatment which will be antibacterially effective. Generally,such antibacterially or therapeutically effective amount of dosage ofactive component (i.e., an effective dosage) will be in the range ofabout 0.1 to about 100, more preferably about 1.0 to about 50 mg/kg ofbody weight/day.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerthat serves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as corn oil,cottonseed oil, sesame oil, coconut oil, or peanut oil, as well aselixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

The following formulation examples illustrate representativepharmaceutical compositions of the present invention.

FORMULATION EXAMPLE 1

Hard gelatin capsules containing the following ingredients are prepared:Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

FORMULATION EXAMPLE 2

A tablet formula is prepared using the ingredients below: QuantityIngredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing240 mg.

FORMULATION EXAMPLE 3

A dry powder inhaler formulation is prepared containing the followingcomponents: Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

FORMULATION EXAMPLE 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows: Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mgStarch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10% solution in sterile water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate  0.5 mg Talc  1.0 mg Total  120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

FORMULATION EXAMPLE 5

Capsules, each containing 40 mg of medicament are made as follows:Quantity Ingredient (mg/capsule) Active Ingredient  40.0 mg Starch 109.0mg Magnesium stearate  1.0 mg Total 150.0 mg

The active ingredient, starch and magnesium stearate are blended, passedthrough a No. 20 mesh U.S. sieve, and filled into hard gelatin capsulesin 150 mg quantities.

FORMULATION EXAMPLE 6

Suppositories, each containing 25 mg of active ingredient are made asfollows: Ingredient Amount Active Ingredient   25 mg Saturated fattyacid glycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

FORMULATION EXAMPLE 7

Suspensions, each containing 50 mg of medicament per 5.0 mL dose aremade as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose(89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Colorq.v. Purified water to  5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

FORMULATION EXAMPLE 8

Quantity Ingredient (mg/capsule) Active Ingredient  15.0 mg Starch 407.0mg Magnesium stearate  3.0 mg Total 425.0 mg

The active ingredient, starch, and magnesium stearate are blended,passed through a No. 20 mesh U.S. sieve, and filled into hard gelatincapsules in 425.0 mg quantities.

FORMULATION EXAMPLE 9

A subcutaneous formulation may be prepared as follows: IngredientQuantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

FORMULATION EXAMPLE 10

A topical formulation may be prepared as follows: Ingredient QuantityActive Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g WhiteSoft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

FORMULATION EXAMPLE 11

An intravenous formulation may be prepared as follows: IngredientQuantity Active Ingredient  250 mg Isotonic saline 1000 mL

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system used for the transport ofbiological factors to specific anatomical regions of the body isdescribed in U.S. Pat. No. 5,011,472 which is herein incorporated byreference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs. Latentiationis generally achieved through blocking of the hydroxy, carbonyl,sulfate, and primary amine groups present on the drug to render the drugmore lipid soluble and amenable to transportation across the blood-brainbarrier. Alternatively, the delivery of hydrophilic drugs may beenhanced by intra-arterial infusion of hypertonic solutions which cantransiently open the blood-brain barrier.

Other suitable formulations for use in the present invention can befound in Remington's Pharmaceutical Sciences,. Mace Publishing Company,Philadelphia, Pa., 17th ed. (1985).

As noted above, the compounds described herein are suitable for use in avariety of drug delivery systems described above. Additionally, in orderto enhance the in vivo serum half-life of the administered compound, thecompounds may be encapsulated, introduced into the lumen of liposomes,prepared as a colloid, or other conventional techniques may be employedwhich provide an extended serum half-life of the compounds. A variety ofmethods are available for preparing liposomes, as described in, e.g.,Szoka, et al., U.S. Pat. Nos. 4,235,871, 4,501,728 and 4,837,028 each ofwhich is incorporated herein by reference.

As noted above, the compounds administered to a patient are in the formof pharmaceutical compositions described above. These compositions maybe sterilized by conventional sterilization techniques, or may besterile filtered. The resulting aqueous solutions may be packaged foruse as is, or lyophilized, the lyophilized preparation being combinedwith a sterile aqueous carrier prior to administration. The pH of thecompound preparations typically will be between 3 and 11, morepreferably from 5 to 9 and most preferably from 7 and 8. It will beunderstood that use of certain of the foregoing excipients, carriers, orstabilizers will result in the formation of pharmaceutical salts.

In general, the compounds of the subject invention will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Toxicity andtherapeutic efficacy of such compounds can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compounds that exhibit large therapeutic indices are preferred.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any compound usedin the method of the invention, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (the concentration of thetest compound which achieves a half-maximal inhibition of symptoms) asdetermined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

Utility

The compounds, prodrugs and pharmaceutically acceptable salts thereof,as defined herein, have activity against at least one of a variety ofbacteria, protozoa, fungi, and parasites. By way of example, thecompounds, prodrugs and pharmaceutically acceptable salts thereof may beactive against gram positive and gram negative bacteria. The compounds,prodrugs and pharmaceutically acceptable salts thereof may be activeagainst a variety of fungi, including fungi from the genus Mucor andCandida, e.g., Mucor racemosus or Candida albicans. The compounds,prodrugs and pharmaceutically acceptable salts thereof may be activeagainst a variety of parasites, including malaria and cyptosporidiumparasite.

The compounds of the subject invention may exhibit activity against atleast one of a variety of bacterial infections, including, for example,gram positive infections, gram negative infections, mycobacteriainfections, mycoplasma infections, and chlamydia infections.

Since the compounds of the subject invention may exhibit potentactivities against a variety of bacteria, such as gram positivebacteria, the compounds of the present invention may be usefulantimicrobial agents and may be effective against at least one of anumber of human and veterinary pathogens, including gram positivebacteria. The Gram positive organisms against which the compounds of thepresent invention may be effective include, for example, Streptococcuspneumoniae, Staphylococcus aureus, Staphylococcus epidermidis,Enterococcus faecalis, Enterococcus faecium, Haemophilus influenzae,Moraxella catarrhalis, Escherichia coli, Bacteroides fragilis,Bacteroides thetaiotaomicron, and Clostridium difficile, and the like.

The compounds of the subject invention may be combined with one or moreadditional antibacterial agents. One or more of the additionalantibacterial agents may be active against gram negative bacteria. Oneor more of the additional antibacterial agents may be active againstgram positive bacteria. The combination of the compounds of the subjectinvention and the one or more additional antibacterial agents may beused to treat a gram negative infection. The combination of thecompounds of the subject invention and the one or more additionalantibacterial agents may be used to treat a gram positive infection. Thecombination of compounds of the subject invention and the one or moreadditional antibacterial agents may also be used to treat a mycobacteriainfection, mycoplasma infection, or chlamydia infection.

The in vitro activity of compounds of the subject invention may beassessed by standard testing procedures such as the determination ofminimum inhibitory concentration (MIC) by agar dilution as described in“Approved Standard. Methods for Dilution Antimicrobial SusceptibilityTests for Bacteria that Grow Aerobically,” 3rd ed., published 1993 bythe National Committee for Clinical Laboratory standards, Villanova,Pa., USA.

The amount administered to the mammalian patient will vary dependingupon what is being administered, the purpose of the administration, suchas prophylaxis or therapy, the state of the patient, the manner ofadministration, and the like. One in example, compositions areadministered to a patient already suffering from a disease in an amountsufficient to cure or at least partially arrest the symptoms of thedisease and its complications. An amount adequate to accomplish this isdefined as “therapeutically effective dose.” Amounts effective for thisuse will depend on the disease condition being treated as well as by thejudgment of the attending clinician depending upon factors such as theseverity of the inflammation, the age, weight and general condition ofthe patient, and the like.

The compositions administered to a patient are in the form ofpharmaceutical compositions described above. These compositions may besterilized by conventional sterilization techniques, or may be sterilefiltered. The resulting aqueous solutions may be packaged for use as is,or lyophilized, the lyophilized preparation being combined with asterile aqueous carrier prior to administration. The pH of the compoundpreparations typically will be between about 3 to about 11, morepreferably from about 5 to about 9 and most preferably from about 7 toabout 8. It will be understood that use of certain of the foregoingexcipients, carriers, or stabilizers will result in the formation ofpharmaceutical salts.

The therapeutic dosage of the compounds of the present invention willvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. For example, for intravenous administration, the dose willtypically be in the range of about 20 μg to about 500 μg per kilogrambody weight, preferably about 100 μg to about 300 μg per kilogram bodyweight. Suitable dosage ranges for intranasal administration aregenerally about 0.1 mg to 1 mg per kilogram body weight. Effective dosescan be extrapolated from dose-response curves derived from in vitro oranimal model test systems.

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention.

EXAMPLES

In the discussion above and in the examples below, the followingabbreviations have the following meanings. If an abbreviation is notdefined, it has its generally accepted meaning.

-   7-methylMTL=1-methylsulfanyl-7-deoxy-7-methyllincosamine-   Ac=acetyl-   apt=apparent triplet-   Aq=aqueous-   atm=atmospheres-   Bn=benzyl-   Boc=tert-butoxycarbonyl protecting group-   br s=broad singlet-   BSTFA=N,O-bis(trimethylsilyl)trifluoroacetamide-   ¹³C NMR=¹³carbon nuclear magnetic resonance-   Cbz=carbonyloxybenzyloxy protecting group-   CDCl₃=deuterated chloroform-   CD₃OD=deuterated methanol-   CD₃SOCD₃=deuterated dimethylsulfoxide-   cfu=colony forming units-   D₂O=deuterated water-   d=doublet-   DAST=dimethylaminosulfurtrifluoride-   dd=doublet of doublets-   dddd=doublet of doublets of doublet of doublets-   DIBALH=Diisobutylaluminum hydride-   dt=doublet of triplets-   DCE=dicholoroethane-   DCM=dichloromethane-   DIEA=diisopropyethylamine-   DMAP=dimethylaminopyridine-   DMF=dimethylformamide-   DMS=dimethyl sulfide-   DMSO=dimethyl sulfoxide-   DPPA=diphenylphosphoryl azide-   ED₅₀=dose therapeutically effective in 50% of the population-   equiv=equivalents-   ESMS=electrospray mass spectrometry-   Et=ethyl-   EtOAc=ethyl acetate-   Et₂O=diethyl ether-   g=grams-   h=hours-   HATU=O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBT=1-hydroxybenzotriazole hydrate-   ¹H NMR=Hydrogen Nuclear Magnetic Resonance spectroscopy-   HPLC=high pressure liquid chromatography-   Hz=hertz-   IC₅₀=concentration of the test compound which achieves a    half-maximal inhibition of symptoms-   J=coupling constant in hertz-   L=liters-   LD₅₀=dose lethal to 50% of the population-   LiHMDS=lithium hexamethyldisilazide-   m=multiplet-   M=molar-   MCPBA=3-Chloroperoxybenzoic acid-   Me=methyl-   MeCN=acetonitrile-   MeOH=methanol-   mg=milligrams-   MHB=Mueller Hinton broth-   MHz=megahertz-   MIC=minimum inhibitory concentration-   min=minutes-   mL=milliliters-   mm=millimeter-   mmHg=millimeters mercury-   mmol=millimol-   MS(ESPOS)=mass spectrometry by positive mode electrospray ionization-   MS(ESNEG)=Mass Spectrometry by negative mode electrospray ionization-   MTBU=7-methyl-1,5,7-triazabicyclo-[4.4.0]dec-5-ene-   MTL=1-methylsulfanyllincosamine (methyl    6-amino-6,8-dideoxy-1-thio-erythro-α-D-galacto-octopyranoside)-   N=normal-   NBS N-bromosuccinimide-   NMR=nuclear magnetic resonance-   OBz=benzyloxy protecting group-   OtBu=tert-butoxy-   Pd/C=palladium/carbon-   pg=picograms-   Ph=phenyl-   Pro=L-proline-   psi=pounds per square inch-   q=quartet-   q.v.=quantitative-   R_(f)=Retention factor-   rt=room temperature-   s=singlet-   sat.=saturated-   t=triplet-   TCI=TCI America-   TEA=triethylamine-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TLC=thin layer chromatography-   TMS trimethylsilyl-   Ts=tosyl-   μg=micrograms-   μL=microliters-   μM=micromolar-   v/v=volume by volume

Additionally, the term “Aldrich” indicates that the compound or reagentused in the following procedures is commercially available from AldrichChemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis.53233 USA; the term “Fluka” indicates that the compound or reagent iscommercially available from Fluka Chemical Corp., 980 South 2nd Street,Ronkonkoma N.Y. 11779 USA; the term “Lancaster” indicates that thecompound or reagent is commercially available from Lancaster Synthesis,Inc., P.O. Box 100 Windham, N.H. 03087 USA; the term “Sigma” indicatesthat the compound or reagent is commercially available from Sigma, P.O.Box 14508, St. Louis Mo. 63178 USA; the term “Chemservice” indicatesthat the compound or reagent is commercially available from ChemserviceInc., Westchester, Pa., USA; the term “Bachem” indicates that thecompound or reagent is commercially available from Bachem BioscienceInc., 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia,Pa. 19406 USA; the term “Maybridge” indicates that the compound orreagent is commercially available from Maybridge Chemical Co.Trevillett, Tintagel, Cornwall PL34 OHW United Kingdom; the term “RSP”indicates that the compound or reagent is commercially available fromRSP Amino Acid Analogs, Inc., 106 South St., Hopkinton, Mass. 01748,USA, and the term “TCI” indicates that the compound or reagent iscommercially available from TCI America, 9211 North Harborgate St.,Portland, Oreg., 97203, OR, USA; the term “Toronto” indicates that thecompound or reagent is commercially available from Toronto ReasearchChemicals, Inc., 2 Brisbane Rd., New York, ON, Canada M3J2J8; the term“Alfa” indicates that the compound or reagent is commercially availablefrom Johnson Matthey Catalog Company, Inc. 30 Bond Street, Ward Hill,Mass. 01835-0747; and the term “Nova Biochem” indicates that thecompound or reagent is commercially available from NovaBiochem USA,10933 North Torrey Pines Road, P.O. Box 12087, La Jolla Calif.92039-2087.

In the examples below, all temperatures are in degrees Celsius (unlessotherwise indicated) and the following general procedures are used toprepare the compounds as indicated.

General Procedures

Method A

Methyl 6-amino-6,8-dideoxy-1-thio-erythro-α-D-galacto-octopyranoside 1a(MTL) was prepared as described by Hoeksema, H. et. al. Journal of theAmerican Chemical Society, 1967, 89, 2448-2452.N-(Benzyloxycarbonyloxy)succinimide (5.8 g 23.1 mmol) and 1a (5.0 g,19.7 mmol) were suspended in pyridine (40 mL) and stirred under N₂atmosphere for 36 h. The reaction mixture was cooled to 0° C. and thenbis-N,O-trifluoroacetamide (15.7 mL, 59.0 mmol) was added by syringeover 2 min. The reaction mixture was allowed to warm to rt and stirredfor 42 h. Toluene (100 mL) was added and the reaction mixture wasevaporated to dryness. The residue was taken up in ethyl acetate (400mL). The organic solution was washed quickly with 10% citric acid (200mL), H₂O (3×100 mL), saturated NaHCO₃ (100 mL), and brine (2×100 mL),and dried over Na₂SO₄ and evaporated to dryness. Chromatography of thecrude product on silica 10% EtOAc/hexanes containing 0.2% TEA afterco-evaporation from toluene (100 mL) and cyclohexane (2×100 mL) providedthe protected product 1b (P=Cbz, R1=SMe) (7.2 g, 54%) as a colorlessoil: ¹H NMR (300 MHz, CD₃SOCD₃) δ 7.34-7.31 (m, 5), 7.05 (d, J=8.2, 1),5.19 (d, J=5.8, 1), 5.01 (d, J=1.6, 2), 3.99 (apt dt, J=5.5, 9.3, 9.3,2), 3.93-3.86 (m, 3), 3.49 (dd, J=2.5, 9.6, 1), 2.01 (s, 3), 1.03 (d,J=6.3, 3), 0.10 (s, 9), 0.09 (s, 9), 0.04 (m, 18).

To dimethylsulfoxide (413 μL, 5.82 mmol) in DCM (1.5 mL) cooled to −72°C. was added oxalyl chloride 2 M in DCM (1.49 mL, 2.98 mmol) over 1 min.After 25 min the protected product 1b (1.92 g, 2.84 mmol) in DCM (4.0mL) was added by cannula. The resulting reaction mixture was stirred 25min and then allowed to warm to −50° C. (dry ice acetonitrile) andmaintained at this temperature for 2 h. To the reaction mixture wasadded TEA (1.29 mL, 3.30 mmol). After 25 min the reaction mixture wasdiluted with EtOAc (300 mL). The resulting organic solution was washedquickly with 5% citric acid (300 mL), H₂O (2×300 mL), saturated NaHCO₃(100 mL), brine (100 mL) dried over Na₂SO₄ and evaporated to drynesswith the aid of toluene (100 mL) to provide the product 1c. The product1c (P=Cbz, R1=SMe) was obtained as a colorless crystalline solid afterco-evaporation with n-pentane and removal of residual solvent under highvacuum (1.60 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.33 (m, 5), 5.60(m, 1), 5.21 (d, J=5.2, 1), 5.17 (d, J=12.4, 1), 5.08 (d, J=12.4, 1),4.74 (m, 1), 4.16-4.12 (m, 2), 3.87 (d, J=2.2, 1), 3.69 (dd, J=2.5, 9.3,1), 2.01 (br s, 3), 1.90 (s, 3), 0.19 (s, 9), 0.16 (s, 9), 0.15 (s, 9).

Method B

The Boc-protected product 1c (P=Boc, R¹=SMe) may be prepared in generalas outlined below. To 1a (MTL) (Dried at 50° C. high vacuum) (21.8 g, 86mmol) suspended in methanol (200 mL) and TEA (26 mL) was cooled to 0° C.on ice, di-t-butyldicarbonate (57.0 g, 0.26 mol) was added. The reactionmixture was then stirred over night at room temperature. To the reactionmixture was added toluene (100 mL) solvents were removed to a totalvolume of 100 mL leaving a thick suspension to which was addedcyclohexane (300 mL). The resulting solid precipitate was trituratedthen filtered and washed with cyclohexane, ether, and pentane and driedto constant weight. The crude Boc-protected product was used withoutfurther purification (87%): TLC R_(f)=0.75 (10% MeOH/DCM); MS (ESPOS):354 [M+H]⁺; ¹H NMR (300 MHz, CD₃OD) δ 0.14 (d, J=6.3, 3), 1.43 (s, 9),2.07 (s, 3), 3.55 (dd, J=3.3, 10.43, 1), 3.84-4.08 (m, 3), 4.10-4.15 (m,2), 5.25 (d, J=5.5, 1).

To N-Boc-1-methylthiolincosamide (240 mg, 0.68 mmol) in DMF (5 mL),BSTFA (0.52 mL, 2.0 mmol) and triethylamine (0.14 mL, 1.42 mmol) wasadded at 0° C. and then left stirred at room temperature over night. DMFwas removed and the crude product was quickly passed through a silicagel column (pretreated with 2% triethylamine in ethyl acetate) elutingwith 10% ethyl acetate in hexanes 1b (P=Boc, R1=SMe) (350 mg, 95%). Tooxalyl chloride (0.16 mL, 0.78 mmol) in dichloromethane (5 mL) at −60°C., dimethylsulfoxide (0.22 mL, 0.78 mmol) was added slowly and thenleft stirred for 15 min. After which, 1b (370 mg, 0.65 mmol) indichloromethane (5 mL) was added slowly. The reaction mixture was leftstirred for 45 min, during which the reaction temperature was increasedto −40° C. Triethylamine (0.70 μL, 3.25 mmol) was then added and thestirring continued for further 15 min at −40° C. It was then extractedwith dichloromethane (100 mL) and washed with 10% citric acid (50 mL).The residue obtained on removal of solvent was then purified on silicagel column using 10% ethyl acetate in hexanes as eluent 1c (P=Boc,R1=SMe) as a colorless oil (289 mg, 78%): TLC: Rf=0.60 (10%EtOAc/hexanes); MS (ESPOS): 590 [M+Na]+; 1H NMR (300 MHz, CDCl3) δ 0.11(s, 18), 0.17 (s, 18), 1.40 (s, 9), 1.84 (s, 3), 2.26 (s, 3), 3.63 (dd,J=2.7, 9.34, 1), 3.82 (d, J=1.9, 1), 4.01-4.12 (m, 2), 5.15 (d, J=5.5,1).

Method C

Triphenylphosphonium bromide (3.29 g, 9.20 mmol) and potassiumtert-butoxide (715 mg, 6.4 mmol) under N₂ atmosphere were suspended intoluene (31 mL) with vigorous stirring. After 4.0 h protected product 1c(P=Cbz, R1=SMe) (1.40 g, 2.36 mmol) in toluene (20 mL) was added bycannula. The resulting reaction mixture was stirred 2 h and then dilutedwith EtOAc (250 mL). The resulting organic solution was washed quicklywith H₂O (2×100 mL), brine (1×100 mL) dried over Na₂SO₄ and evaporatedto dryness. Chromatography of the crude product on silica 6%EtOAc/hexanes containing 0.2% TEA gave the alkene product 2a (P=Cbz,R1=SMe, R^(2′)=H) as a colorless oil that crystallized afterco-evaporation from toluene and cyclohexane (0.65 g, 46%): ¹H NMR (300MHz, CDCl₃) δ 7.35-7.27 (m, 5), 6.36 (d, J=7.1, 1), 5.24 (d, J=5.5, 1),5.08 (m, 4), 4.34 (m, 1), 4.16 (m, 2), 3.88 (d, J=2.2, 1), 3.61 (dd,J=2.2, 9.3, 1), 2.20 (s, 3), 1.79 (s, 3), 0.17-0.13 (m, 27).

The product 2a (P=Cbz, R1=SMe, R^(2′)=H) (490 mg, 0.82 mmol) in ethanol(50 mL) was added to 10% Palladium on carbon (degusa wet form 50% w/wwater) (700 mg) in a parr bottle. The bottle was purged, and chargedwith H₂ to 65 psi and shaken 24 h. The reaction mixture was filteredthrough celite, rinsed with methanol. The organic solution wastransferred to a resin funnel containing dry, washed Dowex® 50w-400xH⁺form (0.8 g) and shaken 10 min. After washing the resin with methanolthree times and water two times, the saturated product 2b was elutedfrom the resin by washing with 5% TEA in MeOH (35 mL×10 min×5). Thecombined filtrate was evaporated to dryness, co-evaporated from EtOHtwice and lyophilized from 1:1 MeCN/H₂O to give the product 2b(R^(2′)=H) as a colorless powder (198 mg, 96%): ¹H NMR (300 MHz, D₂O) δ5.17 (d, J=5.8, 1), 3.97-3.84 (m, 3), 3.52 (dd, J=3.0, 10.0, 1), 2.82(dd, J=4.4, 8.5, 1), 1.94 (s, 3), 1.89-1.81 (m, 1), 0.82 (d, J=6.9, 3),0.72 (d, J=6.9, 3); MS (ESPOS): 252.2 [M+H]⁺, (ESNEG): 250.4 [M−H]⁻.

Method D

In the alternative, when a Boc-protecting group is used in Scheme 1(P=Boc), methyltriphenyl-phosphonium bromide (12 g, 33.6 mmol) andpotassium t-butoxide (3 g, 26.7 mmol) were taken in THF (70 mL) at 0°C., and stirred at rt for 4 h. Then Boc-protected product 1c (P=Boc,R1=SMe) (4.7 g, 8.2 mmol) in THF (30 mL) was added and stirred at rt for2 h. After which it was extracted with EtOAc (300 mL), washed with brine(100 mL) and dried over sodium sulfate. The crude alkene product 2a(P=Boc, R1=SMe, R^(2′)=H) was purified on silica gel columnchromatography using 10% EtOAc in Hexane as eluent (4.1 g, 87.6%): TLC:R_(f)=0.5 (10% of EtOAc in Hexane): ¹H NMR (300 MHz, CD₃OD) δ 7.24 (m,2), 5.22 (d, J=5.7, 1), 4.21 (m, 1), 4.09 (m, 2), 3.87 (d, J=2.4, 1),3.60 (dd, J=2.7, 9.3, 1), 1.99 (s, 3), 1.76 (s, 3), 1.43 (s, 9); MS(ESPOS): 444 [M−2TMS+Na]⁺.

To the product 2a (P=Boc, R1=SMe, R^(2′)=H) in methanol (30 mL), Dowex®H⁺ resin (1 g) was added and stirred at rt for 1 h. The resin wasfiltered and the product obtained on removal of solvent (2.4 g, 6.8mmol,) was taken in MeOH (30 mL), Pd/C (2.5 g) was added andhydrogenated at 55 psi overnight. The crude product obtained onfiltering and removal of solvent was purified on silica gel columnchromatography using 10% MeOH in DCM to provide Boc-protected 7-MethylMTL as a white solid (2.06 g, 86%): TLC R_(f)=0.5 (10% of MeOH in DCM);¹H NMR (300 MHz, CD₃OD) δ 5.23 (d, J=5.4, 1), 4.11 (m, 1), 3.97 (d,J=10.2, 1), 3.84 (m, 1), 3.52 (m, 1), 2.08 (s, 3), 1.44 (s, 9), 1.14 (m,1), 0.93 (d, J=6.9, 3), 0.85 (d, J=6.9, 3); MS (ESPOS): 351 [M+H]⁺.

To Boc-protected 7-Methyl MTL (150 mg, 0.43 mmol) in dichloroethane (6mL), dimethylsulfide (0.16 mL, 2.5 mmol) was added, followed by TFA (2mL), water (0.16 mL) and stirred at rt for 1 h. The solvent was removedto obtain the crude product 2b (R¹=SMe, P=Boc, R^(2′)=H). Afterpurification on silica gel column chromatography using 30% MeOH in DCMas eluent, the product 2b (R^(2′)=H) was obtained identical in allrespects to the material obtained from Method C.

Method E

Sodium hydride (80 mg, 3.3 mmol) under N₂ atmosphere was suspended inTHF (4 mL) with vigorous stirring. The suspension was cooled to −30° C.and diethyl(cyanomethyl)phosphonate (805 μL, 5.0 mmol) was added. After30 min, protected product 1c (P=Cbz, R1=SMe) (1.0 g, 1.7 mmol) in THF (3mL) was added by cannula. The resulting reaction mixture was stirred 4 hand then diluted with EtOAc (250 mL). The resulting organic solution waswashed quickly with saturated aqueous NaHCO₃ (1×100 mL), brine (1×50 mL)dried over Na₂SO₄ and evaporated to dryness. Chromatography of the crudeproduct on silica 6% EtOAc/hexanes to 10% EtOAc/hexanes containing 0.2%TEA gave the protected alkene product 2a (P=Cbz, R1=SMe, R^(2′)=CN) as acolorless oil (0.38 g, 37%): MS (ESPOS): 625.5 [M+H]⁺, MS (ESNEG): 659.5[M+Cl]⁻.

The product 2a (P=Cbz, R¹=SMe, R^(2′)=CN) (180 mg, 0.29 mmol) in ethanol(15 mL) was added to 10% Palladium on carbon (degusa wet form 50% w/wwater) (300 mg) in a Parr bottle and concentrated HCl (29 μL) was added.The bottle was purged, and charged with H₂ to 65 psi and shaken 24 h.The reaction mixture was filtered through celite, rinsed with methanol.The organic solution was transferred to a resin funnel containing dry,washed Dowex® 50w-400x H⁺ form (1 g) and shaken 10 min. After washingthe resin with methanol twice and water, the saturated product 2b(R¹=SMe, R^(2′)=CN) was eluted from the resin by washing with 5% TEA inMeOH (20 mL×20 min×3) and MeCN (20 mL×20 min). The combined organicfiltrate was evaporated to dryness lyophilized from 1:1 MeCN/H₂O to givethe product 2b (R¹=SMe, R²=CH₂CN) as a colorless solid (70 mg, 91%): MS(ESNEG): 275.3 [M−H]⁻.

Method F

To the protected product 1c (P=Cbz, R¹=SMe) (0.75 g, 1.3 mmol) in THF(7.3 mL) was added MeMgCl 3 M (Aldrich) in THF (7.0 mL 2.1 mmol) at 0°C. Over 30 min the reaction mixture was warmed to 4° C. and after 4 hthe reaction mixture was quenched with 1:3 saturated aqueous NH₄Cl/H₂O(10 mL). The quenched mixture was diluted to 100 mL with water andextracted with DCM (4×50 mL). The combined organic phase was dried andevaporated. The residue was dissolved in 1:2:4 H₂O/HOAc/THF (100 mL) andstirred 20 h, and then evaporated with the aid of toluene (2×100 mL).Chromatography (10:1 to 10:2 DCM/MeOH) gave product 3a (P=Cbz, R¹=SMe,R^(2″)=Me) (153 mg, 31%): MS (ESNEG): 399.5 [M−H]⁻.

3a (P=Cbz, R¹=SMe, R^(2″)=Me) (79 mg, 0.2 mmol) in ethanol (10 mL) wasadded to 10% Palladium on carbon (degusa wet form 50% w/w water) (400mg) in a Parr bottle. The bottle was purged, and charged with H₂ to 65psi and shaken 6 h. The reaction mixture was filtered through celite,rinsed with methanol. The combined filtrate was evaporated to drynessand lyophilized from 1:1 MeCN/H₂O to give the product 3b (R¹=SMe,R^(2″)=Me) as a colorless powder (42 mg, 80%): ¹H NMR (300 MHz, D₂O) δ5.33 (d, J=5.8, 1), 4.83-4.06 (m, 3), 3.65-3.60 (m, 1), 3.06-3.03 (m,1), 2.18 (s, 3), 1.30 (s, 3), 1.23 (s, 3); MS (ESPOS): 268.4 [M+H], MS(ESNEG): 266.2 [M−H]⁻.

Method G

To the Boc-protected product 1c (P=Boc, R¹=SMe) (100 mg, 0.18 mmol) inmethanol (3 mL), O-trimethylsilylhydroxylamine (0.10 mL, 0.88 mmol) wasadded and stirred at rt overnight. The solvent was removed to obtain thecrude Boc-protected product 4a (R¹=SMe, R⁷=H). To the crude product 4a(95 mg, 0.15 mmol), 30% triflouoroacetic acid in dichloroethane (10 mL)and dimethyl sulfide (0.5 mL) were added and stirred for 1 h. Thesolvent was removed and the product 4b (R¹=SMe, R⁷=H) was taken as suchfor the next step.

TLC: R_(f)=0.35 (10% MeOH/DCM); MS (ESPOS): 267 (M+H); ¹H NMR (300 MHz,CD₃OD) δ 1.96 (s, 3), 2.09 (s, 3), 3.58 (dd, J=3.3, 10.2, 1), 3.90 (s,1), 4.11 (dd, J=5.7, 10.20, 1), 4.19 (d, J=5.4, 1), 4.50 (d, J=5.1, 1),5.36 (d, J=5.7, 1).

Method H

To the Boc-protected product 1c (P=Boc, R¹=SMe) (100 mg, 0.176 mmol) inmethanol (4 mL) and water (1 mL), O-alkylhydroxylamine hydrochloride(for example, O-methylhydroxylamine hydrochloride) (60 mg, 0.70 mmol)and sodium acetate (57 mg, 0.70 mmol) were added and heated at 80° C.for 3 h and then stirred at rt overnight. The solvent was removed underhigh vacuum to obtain the crude Boc-protected product 4a (R1=SMe,R7=Me). The crude product 4a was taken in 30% trifluoroacetic acid indichloroethane (10 mL), dimethylsulfide (0.5 mL) and stirred for 1 h atrt. The solvent was removed and the residue was kept under high vacuumfor 1 h and the product 4b (R1=SMe, R7 =Me) was taken as such for thenext step: TLC Rf=0.63 (10% MeOH/DCM); MS (ESPOS): 281 [M+H]+; 1H NMR(300 MHz, CD3OD) δ 1.95 (s, 3), 2.08 (s, 3), 3.60 (dd, J=3.3, 10.2, 1),3.92 (s, 3), 4.13 (dd, J=4.8, 10.2, 1), 4.49 (d, J=1.2, 1), 5.38 (d,J=5.4, 1).

Method I

To the Boc-protected product 1c (P=Boc, R¹=SMe) (500 mg, 0.88 mmol) inTHF (10 mL), tetrabutylammonium fluoride (2.5 mmol, 1 M in THF) wasadded and the reaction mixture was stirred at rt for 1 h. The solventwas removed and the residue was purified on silica gel column using 5%methanol in dichloromethane as eluent. The product (111 mg, 0.31 mmol)obtained from the column was then taken in a mixture of dichloromethane(3 mL) and pyridine (3 mL) to which acetic anhydride (0.5 mL, 10.6 mmol)and dimethylaminopyridine (80 mg, 1.7 mmol) were added and stirred at rtovernight. The solvent was removed and the crude product was purified onsilica gel column using 30% ethyl acetate in hexanes as eluent toprovide 5a (P=Boc, R¹=SMe) (58 mg, 38%): TLC R_(f)=0.73 (50%EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 1.38 (s, 9), 1.91 (s, 3), 1.98(s, 3), 2.07 (s, 3), 2.18 (s, 3), 4.33 (m, 1), 4.72 (m, 1), 4.94 (m, 1),5.21 (m, 2), 5.45 (s, 1), 5.57 (m, 1); MS (ESPOS): 500 [M+Na]⁺.

To product 5a (P=Boc, R¹=SMe) (158 mg, 0.331 mmol) in DCM (5 mL),dimethylaminosulfurtrifluoride (732 μL, 3.31 mmol) was added and stirredovernight. More DCM was added and the organic portion was washed withsodium bicarbonate. The residue obtained on removal of solvent waspurified on silica gel column chromatography using 20% ethyl acetate inhexanes as eluent (100 mg, 60%) to provide the protected product (P=Boc,R¹=SMe). The Boc-protected product was taken up in 30% trifluoroaceticacid in dichloroethane and dimethylsulfide and stirred for 1 h at rt.The solvent was removed to provide the product 5b (R¹=SMe): TLCR_(f)=0.63 (40% MeOH/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 1.40 (s, 9),1.69 (t, J=18.9, 3), 1.98 (s, 3), 2.08 (s, 6), 2.13 (s, 3), 4.22-4.30(m, 1), 4.53 (dd, J=10.9, 25.3, 1), 5.16-5.28 (m, 2), 5.52 (s, 1), 5.63(d, J=5.2, 1); MS (ESPOS): 522 [M+Na]⁺.

Method J

Preparation of Compound 6a (P=TFA).

To a 1 L round bottom flask was added dry 1a MTL (R¹=SMe) (dried at 50°C. under vacuum over night) (20 g, 0.079 mol), anhydrous methanol (200mL), triethylamine (8.77 g, 0.087 mol), and methyl trifluoroacetate(127.3 g, 0.99 mol). The reaction mixture was stirred at rt for 4 h,after which the solvent was evaporated to dryness to yield the protectedMTL 6a (R¹=SMe, P=TFA) (26.2 g, 95%), which was taken as such for thenext step.

Chloromethylene Piperidinium HCl (Scheme 6, Reagent b)

To a 3 L 3 necked round bottom flask fitted with a mechanical stirrer,glass stir rod (large Teflon paddle) under a nitrogen atmosphere, wasadded diethyl ether (anhydrous, 1.8 L) and N-formylpiperidine (35.6 g,0.315 mol). The reaction mixture was cooled to 0° C. and triphosgene(31.2 g, 0.105 mol) was added in at least 5 portions over the course of2 hours, maintaining 0° C. and vigorous stirring. The reaction mixturewas then allowed to warm to rt (1 hr) to ensure complete reaction oftriphosgene and then cooled again to 0° C. The reaction mixture was thenfiltered under a stream of nitrogen or argon (very hygroscopic, stench)and washed with cold diethyl ether (2×100 mL). The white crystalsobtained were then dried in vacuum to give chloromethylenepiperidium HCl(46.4 g, 95%).

TFA Protected 7-Cl MTL.

To a 3 L, 3 neck round bottom flask, under a nitrogen atmosphere, fittedwith a mechanical stirrer, glass stir rod, Teflon paddle, and a refluxcondensor, was added chloromethylene piperidinium HCl (44.4 g, 0.286mol) and dichloroethane (anhydrous, 1 L). The resulting slurry wasstirred vigorously and the temperature was brought to 0° C. To thestirring reaction mixture was added the crude 6a (R¹=SMe, P=TFA) (20 g,0.057 mol) over a period of 1 minute. The reaction mixture was stirredfor 1 hr and then the temperature was raised to 65° C., during thisprocess the reaction was seen to turn to a clear solution. The reactionmixture was then stirred at 65° C. for a period of 18 h. The reactionmixture was then cooled to 0° C. and then poured rapidly into a 4LErlenmeyer fitted with a mechanical stirrer, to which had been addedwater (1 L) and NaOH (22.9 g, 0.57 mol,) cooled to 0° C. The reactionmixture was then allowed to stir for a period of 30 min and then the pHwas adjusted to 10.5 (pH paper) with concentrated HCl (added over aperiod of 5 min while pH was checked after each HCl addition, if pH isreduced below 10.5 it is acceptable to simply add NaOH to adjust to10.5. This pH adjusted mixture is then stirred for a period of 2 hourswhile allowing the reaction to come to rt. The pH was then adjusted topH 7 with more concentrated HCl and then allowed to stir overnight, oruntil the product is seen to be free of the adduct formed by thechlorinating agent and the sugar OH functionality. The reaction mixturewas then evaporated to dryness with the aid of high vacuum attached to arotary evaporator (co-evaporating with solvents such as toluene can beused to facilitate this process). To the resulting solid was then addeda mixture of 10% methanol/DCM, and stirred for a period of 1 hour tofree the product from the salts. The mixture was then filtered and thefiltrate was evaporated to dryness to yield syrup containing the productand N-formyl piperidine. The majority of the N-formyl piperidine can beremoved by triturating the mixture with hexanes and decanting the hexanefrom the product oil several times. The crude reaction product was thenchromatographed using 10% methanol/DCM to yield the purified TFAprotected 7-Cl MTL (21.1 g, 75%).

6b (R¹=SMe, R²=Cl, R³=H).

To a 500 mL 3-neck round bottom flask fitted with a mechanical stirrerwas added the purified TFA protected 7-Cl MTL (20 g, 0.054 mol) in aminimal amount of methanol (10 mL), followed by 1 M NaOH, (250 mL) at 0°C. The reaction mixture was then stirred at 0° C. (the mixture was seenat first to form an intractable sticky solid that eventually went intosolution and the pure product crystals were seen to form soon after) for12 hr with periodic harvesting of the pure product crystals to preventhydrolysis of the 7-chloro functionality, and washed with a minimalamount of cold water, followed by cold methanol to furnish 7-Cl MTL 6b(R¹=SMe, R²=Cl, R³=H) as a colorless solid (10 g, 50%).

Method K

Enolization (LiHMDS) and alkylation of 7a with 4-bromo-2-methyl-2-buteneafforded a mixture of diastereomers of the lactam 7b(R^(9′)=2-methyl-2-butene) (61%) according to the literature procedureby Zhang, R.; et. al., Journal of the American Chemical Society. 1998,120, 3894-3902. Compound 7a is commercially available from vendors suchas Bachem. Alternatively, 7a can be prepared by methods well known inthe art, for an example see Baldwin J. E.; et al.; Tetrahedron, 1989,45, 7449-7468.

The lactam 7b was reduced to the pyrrolidine 7c(R^(9′)=2-methyl-2-butene) (70%) by the two-step sequence involvingsuperhydride® reduction of the lactam to the hemiaminal and thesubsequent reduction of the hemiaminal with Et₃SiH/BF₃.OEt₂. Thepyrrolidine 7c (778 mg, 2.08 mmol), 10% palladium on carbon (230 mg), inanhydrous methanol (25 mL) was subjected to Parr hydrogenolysis at 50psi for 5 h. The reaction mixture was filtered through a celite pad andwashed several times with methanol. The combined washings and filtratewere evaporated to dryness, affording, without further purification, acolorless oil 7d (R^(9″)=2-methyl-2-butane): TLC R_(f)=0.3 [Solventsystem: DCM/hexanes/MeOH (6:5:1)]; MS (ESNEG): 284.5 [M−H]⁻.

Method L

To a stirred solution of 7a (9.47 g, 29.7 mmol, 1 equiv) in anhydrousTHF at −78° C. under N2 was added a 1 M solution of LiHMDS in THF (33mmol, 33 mL, 1.1 equiv) followed by cis-1-bromo-2-pentene (4.21 mL, 35.6mmol, 1.2 equiv), afforded a mixture of diastereomers of the lactam 7b(R9′=2-pentene) (43.2%) after silica gel purification. The lactam 7b(3.96 g, 10.22 mmol) was reduced to the pyrrolidine 7c (R9′=2-pentene)by the two-step sequence involving superhydride® reduction of the lactamto the hemiaminal, at −78° C. in anhydrous THF, and the subsequentreduction of the hemiaminal with Et3SiH/BF3OEt2 in anhydrous DCM at −78°C., affording 7c (R9′=2-pentene) (71%) after silica gel purification.The pyrrolidine 7c (2.71 g, 7.26 mmol) and 10% palladium on carbon (560mg) in anhydrous methanol (30 mL) was subjected to Parr hydrogenolysisat 50 psi for 5 h. The reaction mixture was filtered through a celitepad and washed several times with methanol. The combined washings andfiltrate were evaporated to dryness, affording, without furtherpurification, a colorless oil 7d (R9=pentyl) (1.68 g, 80%); TLC: Rf=0.3[Solvent system: DCM:hexanes:MeOH (6:5:1)]. MS (ESNEG): 284.5 [M−H]⁻.

Method M

8a (R^(9′)=3,3-difluoroprop-2-ene).

Ozonolysis treatment of 7c (R^(9′)=2-methyl-2-butene) in anhydrousdichloromethane, followed by treatment with DMS at −78° C., followed byslow warming to rt afforded a terminal aldehyde 8a (77%), which was usedin the next step without further purification.

To a solution of aldehyde 8a from the above reaction (407 mg, 1.17 mmol,1 equiv) in dimethylacetamide (0.25 mL) at 0° C. was addeddibromodifluoromethane (0.21 mL, 2.34 mmol, 2 equiv). To the stirredmixture was added a solution of triphenylphosphine (0.61 g, 2.34 mmol, 2equiv) in dimethyl acetamide (0.5 mL) over a period of 20 minutes undernitrogen. The reaction mixture was warmed to rt and stirred for 30minutes, then was added to an activated zinc (0.25 g, 3.82 mmol, 3.3equiv) with the aid of dimethylacetamide (0.3 mL). The resultingreaction mixture was stirred at 110° C. for 1 h and cooled to rt andfiltered with the aid of dimethylacetamide (7 mL). The filtrate waspoured into an ice water (100 mL) and extracted with ether (150 mL). Theether layer was washed with brine, dried and concentrated. The residuewas purified by chromatography to give a clear oil 8a(R^(9′)=3,3-difluoroprop-2-ene) (182 mg, 41%): MS (ESPOS): 282.4 [MBoc+H]⁺.

8c (R⁹=3,3-difluoroprop-2-ene). To a solution of 8a (84.1 mg, 0.22 mmol,1 equiv) in THF (3 mL) and water (1 mL) was added lithium hydroxidemonohydrate (46.3 mg, 1.10 mmol, 5 equiv). The reaction mixture wasstirred at rt overnight. THF was removed under vacuum. The residue wastaken up in ethyl acetate (50 mL), partitioned with 10% citric acid (20mL). The organic layer was washed with water (1×), brine (1×), dried andconcentrated to provide 8c (R^(9′)=3,3-difluoroprop-2-ene) as a clearglass (56 mg, 87%): MS (ESPOS): 192.3 [M−Boc+H]⁺; MS (ESNEG): 290.3[M−H]−.

8b (R^(9″)=3,3-difluoropropane). The saturated product of Scheme 8 maybe obtained by hydrogenation methods described, for example, in method Kfor 7d.

Method N

9b (P=Boc, m=1, LG=Ts).

To a solution of N-Boc-(2S,4R)-4-hydroxyproline methylester (Bachem) 9a(P=Boc, m=1) (5 g, 20.4 mmol, 1 equiv) and DMAP (0.25 g, 2.04 mmol, 0.1equiv) in DCM (80 mL) was added toluenesulfonic anhydride (8.65 g, 26.5mmol, 1.3 equiv). The reaction mixture was cooled to 0° C. and pyridine(6.59 mL, 81.5 mmol, 4 equiv) was added. The mixture was stirred at 0°C. for 30 minutes and then at rt overnight. The solution wasconcentrated to dryness. The residue was taken up in ethyl acetate (400mL), washed with 10% aq. citric acid (2×400 mL), sat. aq. NaHCO₃ (400mL) and brine, and dried over Na₂SO₄ and concentrated to yield a yellowsyrup 9b (P=Boc, m=1, LG=Ts) (8.44 g, 100%): HPLC (Method RV-1), C18 3.5μm, 4.6 30 mm Column; gradient eluent 2%-98% MeCN over 5 min; 1.5ml/min): Rt=3.096.

9c (P=Boc, m=1, R⁹=2,4-dichlorobenzylsulfide).

To a solution of tosylate 9b (P=Boc, m=1, LG=Ts) (1.02 g, 2.55 mmol, 1equiv) in dry DMF (7.6 mL) under N₂ was added 2,4-dichlorobenzylthiol(1.48 g, 7.66 mmol, 3 equiv), followed by the addition of MTBU (0.55 mL,3.83 mmol, 1.5 equiv). The reaction mixture was stirred at rt overnightand concentrated to dryness. The residue was taken up in ethyl acetate(100 mL), washed with 10% citric acid (50 mL) and brine, andconcentrated. The residue was purified by chromatography to provide aclear syrup, 9c (P=Boc, m=l, R⁹=4-(2,4-dichlorobenzyl sulfide) (1.0 g).MS (ESPOS): 320.2 [M−Boc+]+; MS (ESNEG): 418.4 [M−H]^(−.)

To a solution of methyl ester 9c (P=Boc, m=1,R⁹=2,4-dichlorobenzylsulfide) (1.0 g, 2.38 mmol, 1 equiv) in THF (9 mL)and water (3 mL) was added lithium hydroxide (0.5 g, 11.9 mmol, 5equiv). The reaction mixture was stirred at rt overnight. THF wasremoved under vacuum. The residue was partitioned between ethyl acetate(150 mL) and 10% citric acid (100 mL). The organic layer was washed withwater (1×), brine (1×), dried over Na₂SO₄ and evaporated to give a clearsyrup, 9d (P=Boc, m=1, R⁹=2,4-dichlorobenzylsulfide) (1.0 g): MS(ESPOS): 306.3 [M−Boc+H]⁺; MS (ESNEG): 404.2 [M−H]⁻.

Method O

4-Propylpyridine-2-carboxylic acid 10b (R⁹=n-propyl).

To 4-propylpyridine (TCI) (2.5 g, 20 mmol), 30% hydrogenperoxide (2.4 g)was added and refluxed overnight. The solvent was removed and theresulting residue was taken in DCM (30 mL). Trimethylsilyl cyanide (2.6g, 26 mmol) was added to the above solution followed by dimethylcarbamyl chloride (2.8 g, 26 mmol) and left stirred at room temperatureovernight. Potassium carbonate (10%, 100 mL) was added. The organiclayer was separated, dried over sodium sulfate and then concentrated toobtain 4-propyl-2-cyanopyridine (2.5 g, 93%). It was then refluxed inhydrochloric acid (6N, 60 mL) for overnight. The4-propylpyridinecarboxylic acid 10b (R⁹=nPr) was obtained aftercrystallization from acetonitrile (2.0 g, 71%): MS (ESPOS): 166 [M+H];¹H NMR (300 MHz, CD₃OD) δ 8.75 (dd, J=9.0, 3.0, 1), 8.42 (s, 1), 8.08(dd, J=9.0, 3.0, 1), 3.00 (t, J=7.5, 2), 1.82 (m, 2), 1.05 (t, J=7.2,3).

4-Propyl-(3-phenyl)pyridine-2-carboxylic acid 10b(R⁹=4-propyl-(3-phenyl)).

To 4-propyl-(3-phenyl)pyridine-N-Oxide (1 g, 4.69 mmol) indichloromethane (10 mL) trimethylsilyl cyanide (1.3 mL, 10 mmol) anddimethylcarbamyl chloride (1 mL, 10 mmol) was added and stirred at roomtemperature for 24 hours. Aqueous potassium carbonate (10%, 10 mL) wasadded and extracted with dichloromethane (100 mL). The crude productobtained on removal of solvent was taken in hydrochloric acid (6N, 30mL) and refluxed for 24 hours. Removal of acid followed bycrystallization of the crude product from acetonitrile resulted in acid10b (1 g, 86%): MS (EPOS): 240 [M−1]; ¹H NMR (300 MHz, CD₃OD) δ2.03-2.17 (m, 2), 2.74 (t, J=7.2, 2), 3.04 (t, J=7.8, 2), 7.16-7.38 (m,5), 8.07 (d, J=4.2, 1), 8.40 (s, 1), 8.71 (d, J=5.7, 1).

Method P

4-Chloropicolinic acid methyl ester

A mixture of picolinic acid (20 g, 162 mmol, 1 equiv) and sodium bromide(33.43 g, 325 mmol, 2 equiv) in thionyl chloride (81 mL) was refluxedfor 5 h. The solvent was removed under vacuum. Absolute methanol (160mL) was added and the mixture was stirred at rt for 30 minutes. Thesolvent was evaporated, and the residue was taken up in 5% sodiumbicarbonate and extracted with ethyl acetate (3×). The organic layerswere combined and dried over MgSO₄ and evaporated. The residue waspurified by chromatography to afford 4-chloropicolinic acid methyl ester(19.9 g, 72%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.63 (d,J=5.4, 1), 8.13 (d, J=2.1, 1), 7.48 (dd, J=2.0, 5.3, 1), 4.00 (s, 3).

4-Iodopicolinic acid 11a.

A mixture of 4-chloropicolinic acid methyl ester (2.4 g, 14.1 mmol), 57%hydriodic acid (13.3 mL) and 50% aqueous hypophosphorous acid (0.66 mL)was stirred at 85° C. for 2 h and then was stirred at 107° C. overnight.The mixture was cooled to 95° C. At this temperature were added in 30minutes 10 M sodium hydroxide aqueous solution (4.2 mL), followed by theaddition of water (15.2 mL). The mixture was cooled to rt and stirred atrt for 1 h. The precipitate was filtered, washed with cold water anddried under high vacuum overnight to give a yellow solid 11a,4-Iodopicolinic acid (3.5 g, 66%): ¹H NMR (300 MHz, DMSO d₆) δ 8.39 (d,J=5.1, 1), 8.35 (d, J=1.8, 1), 8.07 (dd, J=1.7, 5.2, 1); MS (ESPOS):250.2 [M+H]⁺.

4-Iodopicolinic acid methyl ester 11b.

To a solution of 4-iodopicolinic acid 11a (7.0 g, 18.6 mmol) in MeOH (70mL) at 23° C. was added concentrated sulfuric acid (350 μL), and thereaction mixture was refluxed for 48 h. The reaction mixture was cooledto room temperature and concentrated to yield the desired product4-iodopicolinic acid methyl ester 11b (4.4 g, 90%) as a yellow oil; ¹HNMR (300 MHz, CDCl₃) δ 8.52 (t, J=0.6, 1.5, 1), 8.40 (d, J=5.1, 1),7.86-7.88 (dd, J=0.6, 5.1, 1), 4.02 (s, 3); MS (ESPOS): 263.9 [M+H];285.9 [M+Na].

4-[3-(tert-Butyl-dimethyl-silanyloxy)-prop-1-ynyl]-pyridine-2-carboxylicacid methyl ester 11c (R^(9′)=tert-butyl-dimethyl-silanyloxy).

To a dry flask was added 11b (5.41 g, 20.6 mmol, 1 equiv),triphenylphosphine (431.5 mg, 1.65 mmol, 0.08 equiv), copper (I) iodide(313.4 mg, 1.65 mmol, 0.08 equiv), palladium acetate (184.5 mg, 0.82mmol, 0.04 equiv) and triethylamine (74 mL). The mixture was degassedwith nitrogen, followed by addition oft-butyldimethyl(2-propynyloxy)silane (Aldrich) (8.34 mL, 41.14 mmol, 2equiv). The mixture was stirred at rt for 3 h. The solvent was removedunder vacuum to give a dark residue. The residue was purified bychromatography to give ester 11c(R^(9′)=3-(tert-butyl-dimethyl-silanyloxy)-prop-1-ynyl) (6.07 g, 97%) asa brown oil: ¹H NMR (300 MHz, CDCl₃) δ 8.67 (dd, J=0.8, 5.0, 1), 8.09(m, 1), 7.43 (dd, J=1.7, 5.0, 1), 4.54 (s, 2), 3.99 (s, 3), 0.92 (s, 9),0.14 (s, 6). MS (ESPOS): 306.5 [M+H]+.

4-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-piperidine-2-carboxylicacid methyl ester 11d(R^(9′)=3-(tert-Butyl-dimethyl-silanyloxy)-propyl).

To a mixture of 11c(R^(9′)=3-(tert-butyl-dimethyl-silanyloxy)-prop-1-ynyl) (6.05 g, 19.8mmol, 1 equiv) in MeOH (60 mL), water (60 mL) and acetic acid (1.14 mL,19.8 mmol, 1 equiv) was added platinum oxide (2.0 g). The mixture waspurged and charged with hydrogen (50 psi) and shaken at rt forovernight. The platinum oxide was removed by filtration and the filtratewas concentrated to give the product 11d(R^(9′)=3-(tert-Butyl-dimethyl-silanyloxy)-propyl) (5.0 g, 80%): MS(ESPOS): 316.6 [M+H]+.

4-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-piperidine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester 11e(R^(9′)=3-(tert-butyl-dimethyl-silanyloxy)-propyl, P=Boc).

To the 11d (R^(9′)=3-(tert-Butyl-dimethyl-silanyloxy)-propyl) (4.99 g,15.8 mmol, 1 equiv) in methanol (60 mL) were added triethylamine (4.42mL, 31.7 mmol, 2 equiv) and di-t-butyldicarbonate (4.7 mL, 20.6 mmol,1.3 equiv). The mixture was stirred at rt overnight. The solvent wasremoved under vacuum. The residue was purified by chromatography to givecarbamate 11e (R^(9′)=3-(tert-Butyl-dimethyl-silanyloxy)-propyl, P=Boc)(2.75 g, 42%) as a clear syrup: ¹H NMR (300 MHz, CDCl₃) δ 4.28 (t,J=6.6, 1), 3.70 (s, 3), 3.55 (t, J=6.3, 2), 3.55-3.48 (m, 1), 3.40-3.30(m, 1), 2.00-1.92 (m, 1), 1.82-1.69 (m, 2), 1.64-1.20 (m, 6), 1.41 (s,9), 0.86 (s, 9), 0.01 (s, 6); MS (ESPOS): 316.6 [M+H−Boc]+.

4-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-piperidine-1,2-dicarboxylicacid 1-tert-butyl ester 11f(R^(9′)=3-(tert-Butyl-dimethyl-silanyloxy)-propyl, P=Boc).

To a mixture of 11e (R^(9′)=3-(tert-Butyl-dimethyl-silanyloxy)-propyl,P=Boc) (2.75 g, 6.63 mmol, 1 equiv) in THF (12 mL) and water (4 mL) wasadded lithium hydroxide monohydrate (306 mg, 7.29 mmol, 1.1 equiv). Themixture was stirred at rt overnight. Additional lithium hydroxidemonohydrate (834 mg, 19.89 mmol, 3 equiv) was added and the mixture wasstirred at rt for 5 hr. THF was removed under vacuum. The aqueous layerwas taken up in ethyl acetate, partitioned with 10% citric acid. Theorganic layer was washed with water (1×), brine (1×), dried andconcentrated to give a yellow syrup which was purified by chromatographyto provide the desired acid 11f(R^(9′)=3-(tert-Butyl-dimethyl-silanyloxy)-propyl, P=Boc) (1.83 g, 69%)as a colorless syrup: ¹H NMR (300 MHz, CDCl₃) δ 4.26 (t, J=6.9, 1), 3.57(t, J=6.5, 2), 3.53-3.44 (m, 1), 3.43-3.33 (m, 1), 2.05-1.96 (m, 1),1.82-1.68 (m, 2), 1.64-1.45 (m, 3), 1.42 (s, 9), 1.37-1.27 (m, 3), 0.86(s, 9), 0.02 (s, 6). MS (ESPOS): 424.7 [M+Na]+.

Method Q

(2S,4R)-N-Boc-4-hydroxyproline methylester.

To a stirred solution of (2S,4R)-4-hydroxyproline (Bachem) (25 g, 108mmol) in methanol (50 mL) at 0° C. was added trimethylsilyldiazomethene(24.6 g, 216 mmol). The mixture was stirred at 0° C. for 1 h. Theresidue obtained on removal of solvent was purified by columnchromatography using 50% ethyl acetate in hexanes to obtain(2S,4R)-N-Boc-4-hydroxyproline methylester (27 g, 100%) as a colorlessoil: ¹H NMR (300 MHz, CDCl₃) δ 4.47 (m, 1), 4.39 (m, 1), 3.70 (s, 3),3.60 (m, 2), 2.27 (m, 1), 2.05 (m, 1), 1.38 (s, 9); MS (ESPOS): 268(M+Na).

(2S,4R)-N-Boc-4-ketoproline methylester 12a (P=Boc, P₂=Me, m=1).

To oxalyl chloride (15 g, 118 mmol) in DCM (15 mL) at −78° C., DMSO(18.6 mL, 236 mmol) was added slowly over 15 minutes. After thecompletion of addition, (2S,4R)-N-Boc-4-hydroxyproline methylester (26.5g, 108 mmol) in DCM (100 mL) was added dropwise and stirred at −78° C.for 20 min, then triethylamine (54.6 g, 540 mmol) was added and leftstirred for 2 h. The reaction mixture was then washed with 10% aq. HCl(200 mL). The organic layer was separated and dried over sodium sulfate.The crude product obtained on removal of solvent was purified by silicagel column chromatography using 50% EtOAc in hexanes to obtain 12a(P=Boc, P2=Me, m=1)-(20 g, 78%) as a brown solid: ¹H NMR (300 MHz,CDCl₃) δ 4.80 (m, 1), 3.88 (d, J=8.7, 2), 3.77 (s, 3), 2.98 (m, 1), 2.58(m, 1), 1.45 (s, 9); MS (ESPOS): 244 (M+H).

N-Boc-4-hydroxy-4-allylproline methylester 12b (P=Boc, P₂=Me, m=1,R^(9′)=allyl).

To a stirred solution of 12a (P=Boc, P₂=Me) (1 g, 4.11 mmol) in THF (10mL), tetraallyltin (1.08 mL, 4.52 mmol) in dry THF was added, thencooled to 0° C. before borontrifluoride etherate (0.520 mL, 4.11 mmol)was added slowly. The mixture was stirred at 0° C. for 1 h and then atroom temperature for an additional 2 h. Potassium fluoride (360 mg in 5mL water) and celite (1 g) was added and the reaction mixture wasstirred for an hour. The reaction mixture was filtered and concentratedto dryness. The residue was dissolved in DCM (200 mL) and washed withwater (100 mL) and brine (100 mL), dried over MgSO₄ and evaporated todryness. The residue obtained was purified by silica gel columnchromatography using 50% EtOAc in hexanes to obtain 12b (P=Boc, P₂=Me,m=1, R⁹=allyl) (0.94 g, 80%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃)δ 5.87 (m, 1), 5.19 (m, 2), 4.34 (m, 1), 3.75 (d, J=4.8, 3), 3.50 (m,3), 2.37 (m, 1), 2.21 (m, 1), 1.39 (d, J=12.9, 9); MS (ESPOS): 308[M+Na]+.

N-Boc-4-fluoro-4-allylproline methylester 12c (P=Boc, P₂=Me, m=1,R^(9′)=allyl).

To a stirred solution of DAST (1.06 g, 6.58 mmol) in DCM (10 mL) at −78°C., 12b (P=Boc, P₂=Me, R⁹=allyl) (940 mg, 3.3 mmol) in dry DCM (10 mL)was added slowly. The mixture was then stirred at −78° C. for 1 h, thenat −10° C. for an additional 1 h. DCM (50 mL) was added, quenched withNH₄Cl (10%, 150 mL), the organic layer was separated, dried over sodiumsulfate and evaporated to dryness. The residue was purified by silicagel column chromatography using 5% EtOAc in hexanes as eluent to providethe desired product 12c (P=Boc, P₂=Me, m=1, R⁹=allyl) (330 mg, 34%) as acolorless oil: ¹H NMR (300 MHz, CDC₁₃) δ 5.82 (m, 1), 5.12 (m, 2), 4.43(m, 1), 3.66 (s, 3), 3.47 (m, 1), 2.37 (m, 1), 2.43 (m, 4), 1.37 (dd,J=4.5, 13.8, 9); MS (ESPOS): 310 [M+Na]+. psN-Boc-4-fluoro-4-propylproline methyl ester 12c (P=Boc, P₂=Me, m=1,R⁹=propyl).

To a solution of 12c (P=Boc P₂=Me, m=1, R⁹=allyl)(0.33 g, 1.15 mmol) inMeOH (15 mL) was added 10% Pd/C (40 mg). The reaction mixture wasstirred at room temperature under hydrogen (30 atm) for 3 hr. Thecatalyst was filtered through celite and washed with methanol. Thefiltrate was concentrated to give the desired protected amino acid ester12c (P=Boc, P₂=Me, R⁹=propyl) (0.33 g, 100%) as a clear oil: ¹H NMR (300MHz, CDCl3) δ 4.43 (m, 1), 3.71 (m, 4), 3.47 (m, 1), 2.51 (m, 1), 1.98(m, 5), 1.40 (dd, J=5.1, 13.8, 9), 0.93 (J=7.8, 3); MS (ESPOS): 190[M−Boc]+.

N-Boc-4-fluoro-4-propylproline 12d (P=Boc, R⁹=propyl, m=1).

To a solution of the methyl ester 12d (330 mg, 1.15 mmol) in THF (12 mL)and water (4 mL), was added lithium hydroxide monohydrate (60 mg, 1.38mmol). The reaction mixture was stirred at room temperature overnight.THF was removed, the residue was taken up in ethyl acetate (50 mL),washed with 10% citric acid (100 mL) and brine (20 mL). Concentration oforganic portion afforded the desired protected amino acid 12e (P=Boc,R⁹=propyl, m=1) (310 mg, 100%) as a white solid: ¹H NMR (300 MHz, CD₃OD)δ 4.43 (m, 1), 3.71 (m, 6), 2.51 (m, 2), 1.98 (m, 3), 1.45 (m, 9), 0.96(m, 3); MS (ESNEG): 274 [M−1]

Method R

(2S,4R)-N-Trifluoroacyl-4-tertbutyloxyproline.

To a solution of 4-tertbutyloxyproline (Bachem) (5.0 g, 27 mmol, 1equiv) and TEA (11.2 mL, 80 mmol, 3 equiv) dry MeOH (30 mL) was addedethyl trifluoroacetate (4.8 mL, 40 mmol, 1.5 equiv). The mixture wasstirred at 24° C. overnight. The solution was concentrated to dryness,dissolved in DCM (200 mL) and the organic phase washed with aq. 0.2 MKHSO4 (2×100 mL) and brine (1×100 mL), dried over MgSO4 and evaporatedto dryness. The resulting residue was titurated with cyclohexane andpentane to provide the product(2S,4R)-N-Trifluoroacyl-4-tertbutyloxyproline as a light yellow powder(5.5 g, 72%).

14a (P=CF₃CO, m=1, R²=H, R³=OH).

To a solution of MTL 1a (1.32 g, 5.3 mmol, 1 equiv) in dry DMF (16 mL)at 0° C. was added triethylamine (2.20 mL, 15.9 mmol, 3 equiv), followedby bis-(trimethylsilyl)trifluoroacetamide (2.81 mL, 10.6 mmol, 2.0equiv). The reaction mixture was stirred at 0° C. for 10 minutes, andthen was stirred at rt for 50 minutes. To the reaction mixture wereadded (2S,4R)-N-Trifluoroacyl-4-tertbutyloxyproline (1.8 g, 6.3 mmol,1.2 equiv), HATU (3.02 g, 8.0 mmol, 1.5 equiv). The reaction mixture wasstirred for 3 h. The reaction mixture was evaporated to dryness, takenup in ethyl acetate (500 mL), washed with 10% citric acid (100 mL),water (100 mL), half sat. aqueous NaHCO₃ (200 mL) and brine. The organiclayer was dried over Na₂SO₄ and evaporated to give a yellow syrup, whichwas dissolved in MeOH (100 mL). Dried Dowex® H+ form resin (500 mg) wasadded and the resulting suspension was stirred for 50 min, filtered, andevaporated to dryness to give a yellow solid (2.89 g). Purification ofthe product by silica chromatography DCM/hexanes/MeOH 6:5:1 to 7:2:1provided product 14a (P=CF₃CO, m=1, R²=H, R³=OH) as a colorless solid(1.7 g, 51%).

14b (P=CF₃CO, m=1, R²=H, R³=OAc).

To a solution of 14a (P=CF₃CO, m=1, R²=H, R³=OH) (1.63 g, 3.1 mmol),pyridine (3 mL, 30 mmol,) and DMAP (38 mg, 0.31 mmol) in dry DCM (10 mL)at 0° C. was added acetic anhydride (3 mL, 31 mmol). The reactiontemperature was allowed to rise to 24° C. over 1 h and stirred 48 h. Thereaction mixture was diluted with chloroform (200 mL) and the organicphase washed with Aq. 10% acetic acid (3×200 mL), 10% citric acid (200mL) half sat. aq. NaHCO₃ (200 mL) and brine (1×100 mL), dried overNa₂SO₄ and evaporated to give the peracylated intermediate 14b (P=CF₃CO,m=1, R²=H, R³=OAc) (2.14 g, 99%) as colorless crystals.

To a solution of the above per-acylated intermediate 14b (P=CF3CO, m=1,R2=H, R3=OAc) (2.1 g, 3.1 mmol) in DCE (64 mL) with methylsulfide (1.4mL) were added trifluoroacetic acid (21 mL) and water (1.4 mL). Thereaction mixture was stirred at rt for 1 h. The solvent was removedunder vacuum and co-evaporated with DCE twice. The residue was purifiedby chromatography 5% MeOH in DCM to provide the intermediate alcohol(1.6 g, 83%) as a colorless solid which was taken to the next stepwithout characterization.

14b (P=CF₃CO, m=1, R²=H, R³=OAc).

To a solution of the above 4-alcohol intermediate (1.5 g, 2.38 mmol, 1equiv) and DMAP (29 mg) in DCE (9.5 mL) was added p-toluenesulfonicanhydride (1.01 g, 3.09 mmol, 1.3 equiv). The reaction mixture wascooled to 0° C. and pyridine (0.77 mL, 9.52 mmol, 4 equiv) was added.The reaction mixture was stirred at 0° C. for 30 minutes then at rtovernight. The reaction mixture was concentrated to dryness. The residuewas taken up in ethyl acetate (200 mL), washed with 10% citric acid(2×200 mL), sat. NaHCO₃ (200 mL) and brine, and dried over Na₂SO₄ andconcentrated to yield a yellow syrup which was purified bychromatography 4:1 hexanes/EtOAc to provide the p-toluenesulfonic esterproduct 14b (P=CF₃CO, m=1, R²=H, R³=OAc) (1.7 g, 92%) as a colorlesssolid.

Method S

Diethyl n-propylmalonate.

To a suspension of sodium hydride (60% dispersion in mineral oil, 12.6g, 315 mmol, 1.05 equiv) in DMF (300 mL) at 23° C. was added a solutionof diethyl malonate (45.5 mL, 300 mmol, 1 equiv) in DMF (100 mL) viacannula over the course of 10 min. The addition caused a mild exothermand H₂ gas evolution was observed, cooling was not necessary. Followingthe addition, the reaction was stirred for 45 min at 23° C. then treatedwith 1-bromopropane (27.3 mL, 300 mmol, 1 equiv). The reaction wasstirred at 23° C. for 25 min, then heated to 65° C. for 3 h, thenstirred at 23° C. overnight. The reaction mixture was added to 1.0 N HCl(1 L) then extracted with diethyl ether (700 mL). The ether extractswere washed with H₂O (400 mL), brine (200 mL), dried (MgSO₄), filteredand concentrated to give 65.1 g of product as a clear oil. ¹³C NMRrevealed approximately 4:1 mono:bis-alkylated product. The productdiethyl n-propylmalonate was used without further purification: ¹H NMR(300 MHz, CDCl₃) 4.18 (q, J=6.9 Hz, 4H), 3.32 (t, J=7.8 Hz, 1H),1.91-1.79 (m, 2H), 1.41-1.25 (m, 2H), 1.25 (t, J=6.9 Hz, 6H), 0.92 (t,J=7.5 Hz, 3H); ¹³C NMR (300 MHz, CDCl₃) (*denotes signal due to minorproduct of bis-alkylation)? 169.6, 61.2, 60.9*, 51.8, 34.4*, 30.7, 20.5,17.3*, 14.4*, 14.0, 13.7.

Ethyl n-propylmalonate 21b (R⁹=n-propyl).

To a solution of diethyl n-propylmalonate (contaminated by approximately20% diethyl bis(n-propyl)malonate, 65.0 g, 273 mmol, 1 equiv) in EtOH(500 mL) at 23° C. was added a solution of 1.0 M KOH (273 mL, 273 mmol,1 equiv). Following the addition, the reaction was heated to 80° C.(internal temperature) for 4 h. After cooling to 23° C. EtOH was removedin vacuo. The residual mixture was partitioned between diethyl ether(400 mL) and H₂O (200 mL). The layers were separated and the ether layerwas extracted with saturated aqueous NaHCO₃ (100 mL). The aqueous NaHCO₃layer was combined with the original aqueous layer and this solution wasacidified to pH 1 with 1.0 N HCl, then extracted with EtOAc (2×600 mL).The EtOAc extracts were dried (MgSO₄), filtered and concentrated to give21b (R⁹=n-propyl) 41.3 g (237 mmol, 79% for 2 steps) of pure product asa clear oil: ¹H NMR (300 MHz, CDCl3) 4.43 (q, J=7.2 Hz, 2H), 3.60 (t,J=7.5 Hz, 1 H), 2.18-2.02 (m, 2), 1.66-1.50 (m, 2 H), 1.49 (t, J=7.2 Hz,3 H), 1.15 (t, J=7.5 Hz, 3 H).

Ethyl n-propylacrylate 21c (R⁹=n-propyl).

To a solution of ethyl n-propylmalonate (41.3 g, 237 mmol, 1 equiv) inEtOH (500 mL) at 23° C. was added piperidine (28.1 mL, 284 mmol, 1.2equiv) followed by aqueous formaldehyde (37%, 88 mL). Following theaddition, the reaction was refluxed for 29 h. After cooling to 23° C.,the mixture was partitioned between diethyl ether (500 mL) and 1.0 N HCl(800 mL). The layers were separated and the aqueous layer was extractedwith diethyl ether (500 mL). The combined organic layers were washedwith H₂O (500 mL), brine (300 mL), dried (MgSO₄), filtered andconcentrated (rotovap only, product is potentially volatile). Theproduct was vacuum distilled (bp 70° C. at 15 mmHg) to give 16.4 g 21c(R⁹=n-propyl) (115 mmol, 49%) of the desired product: ¹H NMR showscontamination with unidentified material; the product was used in thesubsequent step without further purification: ¹H NMR (300 MHz, CDCl₃)6.12 (s, 1H), 5.50 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 2.23 (t, J=7.5 Hz,2H), 1.55-1.42 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.5 Hz, 3H).

2-Propyl-prop-2-en-1-ol.

To a solution of 21c (R⁹=n-propyl) (16.4 g, 115 mmol, 1 equiv) in CH₂Cl₂(500 mL) at 78° C. was added DIBALH (1.0 M in hexanes, 403 mL, 403 mmol,3.5 equiv) via cannula over the course of 20 min. Following theaddition, the reaction was stirred at 78° C. for 30 min, then allowed towarm to 55° C. over the course of 60 min. Once the reaction bathtemperature had reached 55° C., EtOAc (15 mL) was added to quench excessDIBALH. After stirring for 5 min the quenched reaction mixture was addedslowly via cannula to a stirred mixture of 1:1 saturated aqueous sodiumpotassium tartrate:saturated aqueous NaHCO₃ (1 L) at 23° C. The biphasicmixture was stirred for 1 h then the layers were separated. The aqueouslayer was extracted with diethyl ether (500 mL). The combined organiclayers were dried (MgSO₄), filtered and concentrated (rotovap only,product is potentially volatile). The product was vacuum distilled (bp100-120° C. at 15 mmHg) to give 7.58 g (75.8 mmol, 66%) of the desiredproduct 2-Propyl-prop-2-en-1-ol as a clear oil: ¹H NMR (300 MHz, CDCl3)5.22 (s, 1H), 5.06 (s, 1H), 4.27 (s, 2H), 2.24 (t, J=7.5 Hz, 2H),1.75-1.60 (m, 2H), 1.12 (t, J=6.9 Hz, 3H).

2-Bromomethyl-pent-1-ene 21d (R⁹=n-propyl).

To a solution of n-propyl allyl alcohol (7.58 g, 75.8 mmol, 1 equiv) inEt₂O (65 mL) at 0° C. was added pyridine (0.58 mL). A solution of PBr₃(4.28 mL, 45.5 mmol, 0.6 equiv) in Et₂O (20 mL) was then added viacannula over the course of 15 min. Following the addition, the reactionwas stirred at 0° C. for 75 min, then the cold reaction mixture wasadded slowly to stirred ice-cold saturated aqueous NaHCO₃ (500 mL). Theresulting biphasic mixture was extracted with diethyl ether (250 mL).The organic extracts were washed with saturated aqueous NaHCO₃ (2×100mL), brine (100 mL), 1.0 N HCl (100 mL), brine (100 mL), dried (MgSO₄),filtered and concentrated (rotovap at 0° C., product is volatile). Theproduct was purified via flash column chromatography on silica gel usingpentane as eluent to give 5.97 g (36.8 mmol, 49%) of the desired product21d (R⁹=n-propyl) as a clear oil: ¹H NMR (300 MHz, CDCl₃) 5.16 (s, 1H),4.95 (s, 1H), 3.97 (s, 2H), 2.19 (t, J=7.5 Hz, 2H), 1.56-1.43 (m, 2H),0.93 (t, J=7.8 Hz, 3H).

N-Allylglycine ethyl ester.

To a solution of allylamine 21e (R^(9b)=H, m=1) (50 mL, 666 mmol, 2equiv) in Et₂O (167 mL) at 0° C. was added ethyl bromoacetate (36.9 mL,333 mmol, 1 equiv). White precipitate and an exothermic reaction wereobserved immediately upon addition; the exotherm caused the solvent toboil for approximately 2 min. Following the addition, the reaction wasstirred for 2.5 h, then the ice-water bath was removed and the reactionwas stirred at 23° C. overnight. After 15 h at 23° C. the reactionmixture was filtered through a glass frit to remove the precipitatedallylamine hydrobromide salt byproduct. The collected solid was washedwith Et₂O (200 mL), then the combined filtrates were concentrated. Theproduct was vacuum distilled (bp 48-55° C. at 1.0 mm Hg) to give 35.5 g(249 mmol, 75%) of the desired product N-Allylglycine ethyl ester as ayellow oil: ¹H NMR (300 MHz, CDCl₃) 5.93-5.79 (m, 1H), 5.22-5.08 (m,2H), 4.18 (q, J=7.2 Hz, 2H), 3.39 (s, 2H), 3.29-3.23 (m, 2H), 1.27 (t,J=7.2 Hz, 3H); MS (ESPOS): 144.1 [M+H]+.

N-Allylglycine ethyl ester hydrochloride 21f (R^(9b)=H, m=1).

To a solution of N-allylglycine ethyl ester (10.0 g, 70.0 mmol, 1 equiv)in Et₂O (260 mL) and hexane (1.3 L) at 23° C. was slowly added 4.0 M HClin dioxane (16.6 mL, 66.5 mmol, 0.95 equiv) over the course of 35 minvia addition funnel. Following the addition the suspension was stirred afurther 40 min, then the product was isolated via filtration through aglass frit, washing with hexane (200 mL). The collected white solid wastransferred to a flask and placed under vacuum (0.5 mm Hg) for 1 h togive 11.5 g of the desired product as a white solid. The reaction wasrepeated on the same scale to yield a total of 22.73 g (127 mmol, 90%)of the desired amine hydrochloride 21f (R^(9b)=H, m=1) as a white solid:¹H NMR (300 MHz, DMSO-d6) 9.50 (s, 2H), 5.95-5.81 (m, 1H), 5.49-5.37 (m,2H), 4.21 (q, J=7.2 Hz, 2H), 3.92 (s, 2H), 3.59 (d, J=6.6 Hz, 2H), 1.24(t, J=7.2 Hz, 3H); MS (ESPOS): 144.1 [M+H]+.

Pseudoephedrine N-allylglycinamide 21h (R^(9b)=H, m=1).

To a flask containing 21f (R^(9b)=H). (20.3 g, 113 mmol, 1.3 equiv) and(1R, 2R)-pseudoephedrine 21g (14.4 g, 86.9 mmol, 1 equiv) was added THF(130 mL). The resulting mixture was stirred vigorously for 20 minutes at20° C. to give a uniform slurry, then treated with solidlithium-tert-butoxide (9.74 g, 122 mmol, 1.4 equiv) added in a singleportion. The reaction was stirred at 20° C. for 2 d, after which timeanalysis revealed both starting materials were still present. Theincomplete reaction was treated with H₂O (200 mL), then THF was removedin vacuo. The resulting aqueous solution was extracted with CH₂Cl₂ (2150 mL), then saturated with NaCl and further extracted with CH₂Cl₂ (2100 mL). The organic extracts were dried (K₂CO₃), filtered andconcentrated. The crude product was purified via flash columnchromatography on silica gel using 2:2:96 MeOH/Et₃N/CH₂Cl₂ as eluent togive 18 g of product. This material was still substantially contaminatedwith N-allylglycine ethyl ester, this was removed with gentle heating(60° C.) under vacuum (1.0 mmHg) for 15 h to give 14.88 g (56.8 mmol,65%) of the desired glycinamide product 21h (R^(9b)=H, m=1) as a viscousoil: ¹H NMR (300 MHz, CDCl₃) (Spectrum shows rotamers) 7.41-7.24 (m,5H), 6.00-5.80 (m, 1H), 5.29-5.07 (m, 2H), 4.64-4.44 (m, 1H), 3.96-3.84(m, 0.5H), 3.63 (d, J=13.8 Hz, 0.5H), 3.45-3.21 (m, 4H), 2.95 (s, 1.5H),2.78 (s, 1.5H), 1.11 (d, J=6.9 Hz, 1.5H), 0.98 (d, J=6.9 Hz, 1.5H); MS(ESPOS): 263.2 [M+H]+. HPLC (Symmetry C18, 3.5 μm particle size, 100 Åpore size, 4.6 mm diameter 30 mm length, 2%-98% MeCN in H2O w/0.1% TFAover 10 min, 2 mL/min flow rate): Rt=3.10 min.

Alkylation of Pseudoephedrine N-allylglycinamide.

To a flask containing LiCl (flame dried in vacuo, 3.14 g, 74.1 mmol, 4equiv) at 0° C. was added a solution of pseudoephedrineN-allylglycinamide 21h (R^(9b)=H, m=1) (4.85 g, 18.5 mmol, 1 equiv) inTHF (50 mL). The resulting mixture was stirred at 0° C. for 25 min, thentreated with a solution of LiHMDS (1.0 M in THF, 37.0 mL, 37 mmol, 2equiv) added slowly via cannula over the course of 40 min. Following theaddition of LiHMDS, the enolate solution was stirred at 0° C. for afurther 30 min, then allylic bromide (3.00 g, 18.5 mmol, 1 equiv) wasadded dropwise via syringe over the course of 30 sec. The reaction wasstirred at 0° C. for a further 90 min then quenched with H₂O (200 mL)and extracted with CH₂Cl₂ (3×150 mL). The organic extracts were dried(K₂CO₃), filtered and concentrated to give 8.0 g of yellow oil. A smallportion of the crude product was purified via flash columnchromatography on silica gel using (3:2:95 MeOH/Et₃N/CH₂Cl₂) as eluentto provide an analytically pure sample of product. The remainingmaterial was used without any purification in the subsequent step: ¹HNMR (300 MHz, CDCl₃) (Spectrum shows rotamers) 7.40-7.24 (m, 5H),5.90-5.76 (m, 1H), 5.20-5.02 (m, 2H), 4.92-4.75 (m, 2H), 4.66-4.45 (m,2H), 4.20-4.00 (m, 1H), 3.62 (t, J=6.3 Hz, 1H), 3.34-3.16 (m, 1H),3.05-2.94 (m, 2H), 2.84 (s, 3H), 2.55 (q, J=7.2 Hz, 1H), 2.22-1.80 (m,5H), 1.58-1.36 (m, 3H), 1.11 (d, J=6.9 Hz, 2H), 1.04 (t, J=7.2 Hz, 1H),0.96 (d, J=6.9 Hz, 1H), 0.89 (t, J=7.2 Hz, 2H); MS (ESPOS): 345.0[M+H]+. HPLC (Symmetry C18, 3.5 μm particle size, 100 Å pore size, 4.6mm diameter 30 mm length, 2%-98% MeCN in H₂O w/0.1% TFA over 10 min, 2mL/min flow rate): Rt=4.28 min.

Boc-Protection of Diene Amino Amide 21i (R⁹=n-propyl, R^(9b)=H, m=1).

To a solution of amine (crude from previous step, 8.0 g, approximately18 mmol, 1 equiv) in CH₂Cl₂ (100 mL) at 23° C. was added triethylamine(2.83 mL, 20 mmol, 1.1 equiv) followed by (Boc)₂O (8.07 g, 37 mmol, 2equiv). The resulting mixture was stirred at 23° C. for 13.5 h, thenconcentrated. The crude product was purified via gradient flash columnchromatography on silica gel (column packed 5.5 cm diameter 17 cmheight) eluting first with 25% EtOAc/hexanes (1 L), then 30%EtOAc/hexanes (600 mL), then 40% EtOAc/hexanes (400 mL). This provided21i (R⁹=n-propyl, R^(9b)=H, m=1). 5.20 g (11.7 mmol, 65% over 2 steps)of pure product. Some mixed fractions also containing minor amounts ofproduct were discarded: ¹H NMR (300 MHz, CDCl3) (Spectrum showsrotamers) 7.52-7.24 (m, 5H), 5.90-5.62 (m, 1H), 5.44 (t, J=6.9 Hz,0.5H), 5.20-4.96 (m, 2.5H), 4.77 (d, J=13.2 Hz, 2H), 4.68-4.35 (m, 2H),4.00-3.55 (m, 1H), 3.79 (d, J=5.7 Hz, 1H), 2.91 (s, 1H), 2.87 (s, 2H),2.52-2.29 (m, 2H), 2.10-1.96 (m, 2H), 1.54-1.35 (m, 9H), 1.13-1.00 (m,2H), 0.96-0.86 (m, 3H); MS (ESPOS): 467.3 [M+Na]+. HPLC (Symmetry C18,3.5 μm particle size, 100 Å pore size, 4.6 mm diameter 30 mm length,2%-98% MeCN in H₂O w/0.1% TFA over 10 min, 2 mL/min flow rate): Rt=6.85min.

Ring-Closing Diene Metathesis 21j (R⁹=n-propyl, R^(9b)=H, m=1).

To a solution of diene 21i (R⁹=n-propyl, R^(9b)=H) (5.20 g, 11.7 mmol, 1equiv) in CH₂Cl₂ (700 mL) at 23° C. was added benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-(tricyclohexylphosphine)ruthenium(Grubbs 2nd generation catalyst, 320 mg, 0.38 mmol, 0.03 equiv). Thereaction was refluxed for 2 h, then cooled to 23° C. and concentrated.The resulting product was first purified via flash column chromatographyon silica gel (40% EtOAc in hexanes as eluent) to give the desiredproduct still slightly contaminated with unidentified material. Theproduct was then dissolved in hot hexanes (100 mL), and allowed tocrystallize over the course of 2 days. The crystallized product wasisolated via filtration through a glass frit, washing with ice-coldhexane (100 mL), providing 3.425 g of the desired tetrahydropyridine(8.23 mmol, 70%): The mother liquor was concentrated to give 0.57 g ofbrown oil which was again subjected to flash column chromatography onsilica gel (40-50% EtOAc in hexanes as eluent) to give a further 392 mg(0.94 mmol, 8%) of desired product 21j (R⁹=n-propyl, R^(9b)=H, m=1): ¹HNMR (300 MHz, CDCl₃) (spectrum shows rotamers) 7.50-7.25 (m, 5H),5.52-5.26 (m, 1H), 5.05-4.96 (m, 1H), 4.63-4.35 (m, 2H), 4.30-3.58 (m,3H), 2.91 (s, 3H), 2.50-2.34 (m, 1H), 2.20-1.94 (m, 3H), 1.46 (s, 7H),1.41 (s, 2H), 1.19-1.01 (m, 2H), 0.94-0.85 (m, 3H); MS (ESPOS): 439.3[M+Na]+. HPLC (Symmetry C18, 3.5 μm particle size, 100 Å pore size, 4.6mm diameter 30 mm length, 2%-98% MeCN in H2O w/0.1% TFA over 10 min, 2mL/min flow rate): Rt=6.29 min.

Cleavage of Pseudoephedrine Auxiliary 21k (R⁹=n-propyl, R^(9b)=H, m=1).

To a solution of amide 21j (R⁹=n-propyl, R^(9b)=H, m=1) (3.42 g, 8.22mmol, 1 equiv) in MeOH (170 mL) at 23° C. was added 1.0 M aqueous NaOH(41.1 mL, 41.1 mmol, 5 equiv). The reaction was refluxed for 24 h(oil-bath temperature at 100° C.), then cooled to 23° C. andconcentrated via rotary evaporation to remove most of the MeOH. Theresulting aqueous solution was transferred to a separatory funnel,diluted with H₂O (100 mL) and extracted with Et₂O (100 mL). The etherextract was washed with 0.5 M aqueous NaOH (70 mL) then discarded. Thecombined basic aqueous layers were acidified to pH 2 with 1.0 N HCl,then extracted with EtOAc (2 200 mL). The organic extracts were dried(MgSO₄), filtered and concentrated to give 2.46 g of the desiredBoc-protected amino acid 21k (R⁹=n-propyl, R^(9b)=H, m=1): ¹H NMR (300MHz, CDCl₃) (Spectrum shows rotamers) 5.36 (d, J=22.8 Hz, 1H), 5.09 (d,J=4.8 Hz, 0.5H), 4.90 (br s, 0.5H), 4.14-3.97 (m, 1H), 3.83-3.67 (m,1H), 2.57-2.37 (m, 2H), 1.98 (t, J=7.2 Hz, 2H), 1.48 (s, 6H), 1.47-1.35(m, 2H), 1.46 (s, 3H), 0.86 (t, J=7.2 Hz, 3H); MS (ESPOS): 292.1[M+Na]+; MS (ESNEG): 268.2 [M−H]−.

Method T

To anhydrous MeOH (20 mL) at 0° C. was added dropwise SOCl₂ (1.58 mL,21.6 mmol) the solution was stirred at 0° C. for 10 minuets then solidL-2-amino-4-pentenioc acid 22a (R^(9b)=H) (Aldrich) (1.0 g, 8.7 mmol)was added. The reaction mixture was stirred 48 h at ambient temperature,solvents were removed under vacuum. Purification was carried by silicagel column chromatography (10% MeOH/DCM) provide L-2-amino-4-penteniocacid methyl ester 22b (R^(9b)=H) (0.95 g, 85%).

To a solution of L-2-amino-4-pentenioc acid methyl ester indichloroethane (32 mL) at 0° C. was added 2,4,6-collidine (2.3 mL, 19.1mmol, 2.2 equiv) and solid 2-nitrobenzenesulfonyl chloride. The reactionwas stirred for 3 h at r.t. The solvent was removed under vacuum and theresidue was distributed between EtOAc (200 mL) and saturated aqueousNH₄Cl. The organic layer was washed with 1.0 M aq. KHSO₄, saturated aq.NaHCO₃, brine, and dried (MgSO₄), and concentrated to give a residuethat was purified by column chromatography on silica (gradient 10 to 20%EtOAc/hexanes) to give the desired product 22b (R^(9b)=H) 0.70 g (26%)as a yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 8.10-8.06 (m, 1), 7.95-7.92 (m, 1), 7.76-7.73(m, 2), 6.08 (d, J=8.2, 1), 5.74-5.60 (m, 1), 5.17-5.12 (m, 2),4.33-4.26 (m, 1), 3.52 (s, 3), 2.58 (dd, J=6.0, 6.0, 1), 3.44-3.30 (m,2), 2.25-2.10 (m, 2), 2.11 (s, 3), 2.00-1.88 (m, 1), 1.86-1.70 (m, 1),1.44-1.25 (m, 6), 0.98-0.88 (m, 9 H).

MS (ESNEG): 313.0 [M−H]⁻.

To a stirred suspension of sulfonamide 22b (R^(9b)=H) (685 mg, 2.18mmol), Cs₂CO₃ (710 mg, 2.18 mmol), and tetrabutylammonium bromide (702mg, 2.18 mmol), in DMF (5.0 mL) was added a solution of3-methylenehex-1-yl-toluenesulfonate 22c (R⁹=propyl) (702 mg, 2.61 mmol;prepared as described by Kelvin H. Yong et al. Journal of OrganicChemistry, 2001, 66, 8248) in DMF (1.0 mL), the reaction mixture washeated to 60° C. overnight. The reaction solvent was removed byevaporation, the resulting residue taken up in EtOAc and washed with 10%aqueous citric acid and brine, the organic phase was dried over MgSO₄concentrated to give a residue that was purified by columnchromatography on silica (17%-20% EtOAc/hexanes) to give the desiredproduct 22d (R⁹=propyl, R^(9b)=H), (0.38 g, 42%) as an oil.

MS (ESPOS): 433 [M+Na]⁺.

To a solution of 22d (R⁹=propyl, R^(9b)=H) (0.38 g, 0.92 mmol) inanhydrous DCM (40 mL) was addedbenzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro-(tricyclohexylphosphine)ruthenium (23.3 mg, 0.0276 mmol) theresulting reaction mixture was refluxed under N₂ for 2.5 hrs, cooled toroom temperature and concentrated. The product was purified by flashcolumn chromatography on silica gel (35% ethyl acetate/hexanes) to givethe desired compound 22e (R⁹=propyl, R^(9b)=H) (0.29 g, 81%).

MS (ESPOS): 383 [M+Na]⁺.

To a stirred solution of thiophenol (183 μL, 1.79 mmol) and7-methyl-1,5,7-triazabicyclo-[4,4,0] dec-5-ene (214 μL, 1.49 mmol) inanhydrous DMF (3 mL) was added a solution of alkene 22e (R⁹=propyl,R^(9b)=H) (228 mg, 0.596 mmol) in anhydrous DMF (3.0 mL) via a canulathe resulting reaction mixture was stirred under N₂ for one hour thenconcentrated to a residue. The residue was taken up in ether, stirredwith 1N aqueous HCl (15.0 mL) for 5 min. The aqueous phase was washedwith ether then made basic with solid potassium carbonate. The resultingbasic aqueous phase was extracted with ether three times. The combinedorganic layer was washed with brine, dried with anhydrous sodiumsulfate, and concentrated, cooled to 0° C. and treated with 2M HCl inether (0.8 mL) was added and the resulting mixture was stirred for 5 minand then evaporated to dryness to give the desired product 22f(R⁹=propyl, R^(9b)=H) as the hydrochloride salt (144 mg, 103%).

MS (ESPOS): 198 [M+H]⁺.

To a solution of amine 22f (R⁹=propyl, R^(9b)=H) (143 mg, 0.61 mmol) inanhydrous dichrolomethane (2.0 mL) was added triethylamine (170 μL, 1.22mmol) and di-t-butyldicarbonate (350 mg, 1.6 mmol). The resultingreaction mixture was stirred over night at room temperature under N₂then evaporated to dryness and purified by flash column chromatographyon silica gel using 20% ethylacetate in hexanes as an eluent to give thedesired compound 22g (R⁹=propyl, R^(9b)=H) (176 mg, 86%).

MS (ESPOS): 320 [M+Na]⁺.

To a solution of ester 22g (R⁹=propyl, R^(9b)=H) (175 mg, 0.59 mmol) indioxane/water (6:1) (4 mL) was added 1 M aqueous lithium hydroxide (0.65mL, 0.648 mmol). The resulting reaction mixture was stirred over nightat room temperature under N₂ and the solvent was removed under reducedpressure. The residue was taken up in water washed with ether. Theaqueous layer was acidified with 10% citric acid and extracted withether. The organic layer was washed with brine, dried with sodiumsulfate, and evaporated to dryness to give the desired protected cyclicamino acid 22h (R⁹=propyl, R^(9b)=H) (175 mg, 105%).

MS (ESNEG): 292 [M−H]⁻.

General Method U

To a solution of nitrone 23a (prepared as described by Dondoni et al,Synthetic Communications, 1994, 24, 2537-2550) (5.96 g, 16.4 mmol, 1equiv) in Et₂O (200 mL) at 23° C. was added a solution of Et₂AlCl (1.0 Min heptane, 16.4 mL, 16.4 mmol, 1 equiv). The reaction was stirred for15 min at 23° C. then cooled to −78° C. and treated with a solution ofcyclopropylmagnesium bromide (0.5 M in THF, 99 mL, 49 mmol, 3 equiv)added via cannula over the course of 25 min. After stirring for afurther 1.7 h at −78° C. the reaction was quenched at low temperaturewith 1.0 M aqueous NaOH (80 mL). The resulting mixture was stirred at23° C. for 25 min, then transferred to a separatory fimnel and thelayers separated. The organic layer was washed with brine (100 mL, usinggentle agitation to avoid formation of an emulsion). The originalaqueous layer was extracted with Et₂O (3×150 mL), washing each extractwith brine (100 mL). The combined organic layers were dried (MgSO₄),filtered and concentrated to give 5.89 g (14.5 mmol, 89%) of the desiredproduct 23b (R²⁰+R²¹=cyclopropane) as a white solid. This material wasused without further purification.

MS (ESPOS): 406.0 [M+H]

To a solution of hydroxylamine 23b (R²⁰+R²¹=cyclopropane) (5.89 g, 14.5mmol, 1 equiv) and Et₃N (12.2 mL, 87.3 mmol, 6 equiv) in CH₂Cl₂ (200 mL)at 0° C. was added methanesulfonyl chloride (2.25 mL, 29.1 mmol, 2equiv). The reaction was stirred for 20 min at 0° C., then at 23° C. fora further 25 min, then added to 1.0 M aqueous NaOH:brine (1:1, 200 mL).The layers were separated, the aqueous layer was extracted with CH₂Cl₂(2×50 mL), then the combined organics were dried (MgSO₄), filtered andconcentrated. The resulting residue was dissolved in 1:1 EtOAc:hexane(200 mL) and washed with H₂O (150 mL), saturated aqueous NaHCO₃ (200mL), brine (150 mL), dried (MgSO₄), filtered and concentrated to give5.95 g of brown oil of which the major component is the desired imine.

MS (ESPOS): 388.2 [M+H]

To a solution of crude imine (5.95 g) in MeOH (150 mL) at 23° C. wasadded Girard's reagent T (2.84 g, 16.9 mmol, 1.1 equiv). After stirringfor 70 min the solution was concentrated. The residue was partitionedbetween EtOAc (150 mL) and 1:1:1 H₂O:brine:saturated aqueous NaHCO₃ (150mL). The layers were separated, the aqueous layer was extracted withEtOAc (150 mL). The combined organics were dried (MgSO₄), filtered andconcentrated to give 4.70 g of yellow oil of which the major componentis the desired amine.

MS (ESPOS): 300.0 [M+H]⁺.

To a solution of crude amine (4.70 g) and 2,6-lutidine (7.31 mL, 62.9mmol, 4 equiv) in CH₂Cl₂ (200 mL) at 0° C. was added trifluoroaceticanhydride (3.28 mL, 23.6 mmol, 1.5 mmol). The reaction was stirred at 0°C. for 1 h, then at 23° C. for 3 h, then quenched with H₂O (100 mL). Thequenched reaction mixture was stirred for 10 min then partitionedbetween 1:1 EtOAc:hexanes (300 mL) and brine (200 mL). The layers wereseparated, the organic layer was washed with 1.0 N HCl, (300 mL),saturated aqueous NaHCO₃ (300 mL), brine (200 mL), dried (MgSO₄),filtered and concentrated. The product was purified using flash columnchromatography on silica gel using 25% EtOAc in hexanes as eluent toprovide 4.50 g of the desired trifluoroacetamide 23c(R²⁰+R²¹=cyclopropane) (11.3 mmol, 78% from hydroxylamine).

MS (ESPOS): 418.0 [M+Na]⁺

To a solution of diacetonide 23c (R²⁰+R²¹=cyclopropane) (4.50 g, 11.3mmol, 1 equiv) at 23° C. was added aqueous TFA (80%, 100 mL, precooledto 0° C.). The reaction was stirred at 23° C. for 35 min thenconcentrated to provide 3.87 g of white solid of which the majorcomponent is the desired deprotected galactose.

MS (ESPOS): 338.1 [M+Na]⁺

To a solution of crude galactose (3.65 g, 11.6 mmol, 1 equiv) and Et₃N(16.1 mL, 116 mmol, 10 equiv) in CH₂Cl₂ (130 mL) at 23° C. was addedAc₂O (7.65 mL, 81.1 mmol, 7 equiv) followed by DMAP (141 mg, 1.2 mmol,0.1 equiv). The reaction was stirred at 23° C. for 2 h, then quenchedwith MeOH (5 mL). The quenched reaction mixture was stirred for 5 minthen diluted with Et₂O (300 mL). The resulting solution was washed withH₂O (2×300 mL), 1.0 N HCl (300 mL), saturated aqueous NaHCO₃ (300 mL),brine (300 mL), dried (MgSO₄), filtered and concentrated to provide 5.07g of acetylated product as a mixture of both alpha/beta andpyranose/furanose isomers.

MS (ESPOS): 506.1 [M+Na]⁺.

To a solution of peracetate isomers (5.07 g) in CH₂Cl₂ (150 mL) at 0° C.was added a solution of HBr in acetic acid (33%, 30 mL). The reactionwas stirred at 0° C. for 30 min then warmed to 23° C. After stirring afurther 3.5 h, the reaction mixture was diluted with CH₂Cl₂ (50 mL),washed with ice-water (2×300 mL), ice-cold 50% saturated aqueous NaHCO₃(2×300 mL), ice-cold 50% saturated brine (300 mL), dried (MgSO₄)filtered and concentrated to provide 4.33 g of the α-bromide 23d(R²⁰+R²¹=cyclopropane) (8.60 mmol, 76% from diacetonide). This materialwas used without further purification.

To a solution of bromide 23d (R²⁰+R²¹=cyclopropane) (4.33 g, 8.60 mmol,1 equiv) in AcOH (100 mL) at 23° C. was added AgOAc (1.44 g, 8.60 mmol,1 equiv). After stirring for 45 min at 23° C., the reaction mixture wasdiluted with CH₂Cl₂ (350 mL) and washed with H₂O (2×400 mL), ice-cold50% saturated aqueous NaHCO₃ (3×300 mL), brine (400 mL), dried (MgSO₄),filtered and concentrated to give 3.76 g (7.78 mmol, 91%) of the desiredβ-acetate as a white foam. This material was used without furtherpurification.

MS (ESPOS): 506.1 [M+Na]

To a solution of β-acetate (3.76 g, 7.78 mmol, 1 equiv) in CH₂Cl₂ (50mL) at 23° C. was added PCl₅ (1.70, 8.17 mmol, 1.05 equiv) followed byBF₃.OEt₂ (50 μL). After stirring for 1 h the reaction was diluted withCH₂Cl₂ (300 mL) and washed with ice-cold brine (500 mL), ice-cold 50%saturated aqueous NaHCO₃ (2×500 mL), ice-cold brine (500 mL), dried(MgSO₄), filtered and concentrated to give 3.72 g of the desiredβ-chloride 23e (R²⁰+R²¹=cyclopropane). The product was used withoutfurther purification.

MS (ESNEG): 458.2 [M−H]

To a solution of galactosyl chloride 23e (R²⁰+R²¹=cyclopropane) (3.72 g,8.10 mmol, 1 equiv) in DMF (30 mL) and HMPA (7.5 mL) at 23° C. was addedMeSNa (1.70 g, 24.3 mmol, 3 equiv). After stirring for 35 min at 23° C.,the reaction mixture was partitioned between Et₂O (150 mL) and 1:1H₂O/brine (70 mL). The layers were separated, the aqueous layer wasre-extracted with Et₂O (150 mL). The combined organics were dried(MgSO₄), filtered and concentrated. The residue was dissolved in CH₂Cl₂(130 mL) and treated with Et₃N (11.3 mL, 81.0 mmol, 10 equiv), Ac₂O(5.35 mL, 56.7 mmol, 7 equiv), and DMAP (99 mg, 0.81 mmol, 0.1 equiv).After stirring for 1 h at 23° C. the reaction was quenched with MeOH(3.0 mL). The quenched reaction mixture was stirred for 10 min thenpartitioned between Et₂O (200 mL) and H₂O (200 mL). The layers wereseparated, the organic layer was washed with 1.0 M aqueous HCl (200 mL),saturated aqueous NaHCO₃ (200 mL), brine (100 mL), dried (MgSO₄),filtered and concentrated. The crude product was purified via flashcolumn chromatography on silica gel using 30% EtOAc in hexane as eluentto give 2.03 g (4.30 mmol, 53%) of the desired product 23f(R²⁰+R²¹=cyclopropane, R¹=SMe) as a white solid.

¹H NMR (300 MHz, CDCl₃) β 6.52 (br d, J=9.3 Hz, 1 H), 5.65 (d, J=5.4 Hz,1 H), 5.56 (dd, J=0.9, 3.0 Hz, 1 H), 5.27 (dd, J=5.4, 11.1 Hz, 1 H),5.20 (dd, J=3.0, 10.5 Hz, 1 H), 4.43 (dd, J=0.9, 7.5 Hz, 1 H), 3.66 (q,J=9.0 Hz, 1 H), 2.15 (s, 3 H), 2.08 (s, 3 H), 2.07 (s, 3 H), 1.98 (s, 3H), 0.94-0.78 (m, 1 H), 0.70-0.61 (m, 1 H), 0.57-0.33 (m, 3 H); MS(ESPOS): 493.9 [M+Na]; MS (ESNEG): 470.2 [M−H]⁻.

To a solution of triacetyl trifluoroacetamide 23f (R²⁰+R²¹=cyclopropane,R¹=SMe) (2.03 g, 4.30 mmol, 1 equiv) in MeOH (35 mL) at 23° C. was added1.0 M aqueous NaOH (43 mL, 43 mmol, 10 equiv). The reaction was stirredfor 100 min, then acidified to pH 2 with 1.0 M aqueous HCl (48 mL). Theresulting solution was concentrated to dryness in vacuo, then theresidue was dissolved/suspended in EtOH (40 mL) and filtered through amedium porosity glass frit to remove NaCl. The solid was washed withEtOH (2×20 mL). The combined filtrate was treated with Amberlite IRA400(OH⁻ form) resin (60 mL resin bed in MeOH), transferring the resin withMeOH (2×20 mL). The resulting mixture was stirred at 23° C. for 1 h thenfiltered. The resin was washed with MeOH (3×100 mL), CH₃CN (100 mL). Thecombined filtrate was concentrated to give 1.04 g of the desiredgalactoside 23 g (R²⁰+R²¹=cyclopropane, R¹=SMe) as a white solid (4.19mmol, 97%). The product was used without further purification.

¹H NMR (300 MHz, CD₃OD) β 5.28 (d, J=5.7 Hz, 1 H), 4.13-4.06 (m, 2 H),3.97 (d, J=6.6 Hz, 1 H), 3.59 (dd, J=3.3, 9.9 Hz, 1 H), 2.33 (dd, J=6.9,9.0 Hz, 1 H), 2.05 (s, 3 H), 0.91-0.77 (m, 1 H), 0.58-0.43 (m, 2 H),0.39-0.31 (m, 1 H), 0.28-0.19 (m, 1 H); MS (ESPOS): 272.0 [M+Na]; MS(ESNEG): 248.2 [M−H].

General Method V

Following the general method in Scheme 24, to a solution of the compound1 hydrochloride (9.90 mmol, 1 equiv) in THF (70 mL) at 23° C. was addedH₂O (70 mL) followed by KHCO₃ (12.9 mmol, 1.3 equiv) followed by (Boc)₂O(12.9 mmol, 1.3 equiv). After stirring for 5 h, the reaction mixture waspartitioned between brine (200 mL) and EtOAc (300 mL). The organic layerwas separated and washed with brine (150 mL), and dried (MgSO₄). Solventwas removed under vacuum and the crude product purified using Biotage®column chromatography system (40+M cartridge, 40 mm ID×150 mm) using alinear gradient (75% EtOAc/hexanes-100% EtOAc) over 1.2 L total eluentat 50 mL/min to give of the carbamate 24a (8.91 mmol, 90%).

To a solution of carbamate 24a (15.9 mmol, 1 equiv) in benzene (300 mL)at 23° C. was added p-anisaldehyde dimethyl acetal (4.06 mL, 23.8 mmol,1.5 equiv), followed by PPTS (199 mg, 0.79 mmol, 0.05 equiv). Thereaction mixture was heated to reflux. After 4 h a second portion ofp-anisaldehyde dimethyl acetal (2.0 mL, 11.7 mmol, 0.74 equiv) wasadded. After a further 17 h a third portion of p-anisaldehyde dimethylacetal (2.0 mL, 11.7 mmol, 0.74 equiv) was added. Following the finaladdition the reaction was refluxed a further 3 h then cooled to 23° C.and partitioned between EtOAc (300 mL) and H₂O (300 mL). The organiclayer was washed with 50% saturated aqueous NaHCO₃ (300 mL), brine (150mL), dried (MgSO₄), filtered and concentrated. The crude product waspurified via silica gel flash column chromatography using 40% EtOAc inhexane as eluent to give acetal 24b (11.3 mmol, 71%).

To a solution of alcohol 24b (4.82 mmol, 1 equiv) in trimethyl phosphate(60 mL) at 0° C. was added pyridine (3.90 mL, 48.2 mmol, 10 equiv),followed by POCl₃ (0.88 mL, 9.65 mmol, 2 equiv) added over the course of60 sec. Other acylating reagents such as acid anhydrides (R¹¹CO)₂O oracid chlorides R¹¹COCl in the presence of an appropriate base may beused in this step to provide different R¹¹ acyl substituents. Followingthe addition, the reaction was maintained at 0° C. for 2 h, thentriethylammonium bicarbonate buffer (1.0 M, pH 8.5, 40 mL) was addedcarefully to quench the reaction. H₂O (60 mL) was then added, and theresulting mixture was stirred at 0° C. for 30 min then warmed to 23° C.After stirring the quenched reaction mixture for 2 h at 23° C.,volatiles were removed in vacuo with aid of gentle heating in water bath(40-45° C.). The resulting crude product was azeotropically dried byco-evaporation with DMF (3×100 mL), then toluene (150 mL, bathtemperature=40-45° C.) to provide of white solid. The crude product 24c(R¹¹=PO(OH)₂) was substantially contaminated with triethylammoniumsalts, but was carried forward without purification.

To a solution of the protected phosphate 24c (R¹¹=PO(OH)₂) prepared asdescribed above (crude from previous step, approximately 4.8 mmol) in1,2-dichloroethane (600 mL) at 0° C. was added H₂O (25 mL) followed byTFA (200 mL). Following the additions, the reaction was maintained at 0°C. for 5 min then warmed to 23° C. After stirring for 25 min at 23° C.,volatiles were removed in vacuo to give 16.2 g of oil. The crude productwas dissolved in 1:1 H₂O/MeOH (70 mL), filtered and the resultingsolution was purified by preparative HPLC (Waters Nova-Pak® HR C₁₈, 6 μmparticle size, 60 Å pore size, 40 mm ID×200 mm, 5-60% acetonitrile inH₂O w/0.1% AcOH over 30 min, 75 mL/min flow rate) to give the desired2-phosphate 5 (R¹¹=PO(OH)2) (3.10 mmol, 64% from free alcohol) as awhite solid.

Method W

To a solution of β-lactam 25a (2.92 g, 12.8 mmol) 1 equiv; prepared frombenzyl (S)-(−)-4-oxo-2-azetidine-carboxylate (Aldrich) as described byBaldwin et al, Tetrahedron, 1990, 46, 4733 in THF (30 mL) at 0° C. wasadded a solution of LDA (2.0 M, 14.0 mL, 28.1 mmol, 2.2 equiv) viasyringe pump over 20 min. The reaction was stirred at 0° C. for 30 min.crotyl bromide (85%, 2.89 mL, 28.1 mmol, 2.2 equiv) was added dropwiseover ca. 1.5 min, and the mixture was stirred for 2 h at 0° C., and thenpartitioned between 1.0 M aqueous KHSO₄ (100 mL) and EtOAc (100 mL). Theorganic layer was separated and washed with 1.0 M aqueous KHSO₄ (100mL), brine (100 mL), dried (MgSO₄), filtered and concentrated to give25b (R^(9′)=2-butenyl) 3.65 g (100%) of greenish yellow solid. Thismaterial was used without further purification.

MS (ESNEG): 282.2 [M−H]⁻.

Trimethylsilyldiazomethane (2.0 M in Et₂O, 25.0 mL, 50 mmol, 3.9 equiv)was slowly added to a solution of acid 25b (R^(9′)=2-butenyl) (3.65 g,12.9 mmol, 1 equiv) in methanol (70 mL) at 0° C. Solvent was removedunder vacuum to give 3.53 g (11.9 mmol, 92%) of the desired esterproduct as a yellow oil. This material was used in the subsequentreaction without further purification.

To a solution of alkene 25c (R^(9′)=2-butenyl) (3.53 g, 11.9 mmol, 1equiv) in EtOAc (40 mL) at 23° C. was added Pd/C (10 wt. %, 482 mg). Thereaction vessel was charged with hydrogen (balloon), and the mixturestirred vigorously. After 2.5 h, the reaction mixture was filteredthrough a pad of Celite. Celite was washed, with EtOAc (200 mL) and thefiltrate was concentrated to provide 3.51 g (11.7 mmol, 99%) of 25c(R⁹=butyl) as a yellow oil. This material was used without furtherpurification.

MS (ESPOS): 300.4 [M+H]⁺.

To a solution of N-TBS β-lactam 25c (R⁹=butyl) (3.51 g, 11.7 mmol, 1equiv) in THF (50 mL) at 23° C. was added Et₃N.3HF (0.95 mL, 5.85 mmol,0.5 equiv). After stirring for 60 min at 23° C., the reaction mixturewas partitioned between 90% saturated brine (150 mL) and EtOAc (200 mL).The organic layer was separated and washed with brine (150 mL), dried(MgSO₄), filtered and concentrated. The product was purified via flashcolumn chromatography on silica gel using 50% EtOAc in hexane as eluentto give 1.48 g (8.0 mmol, 68%) of 25d (R⁹=butyl) as a clear oil.

MS (ESPOS): 578.3 [3M+H]⁺.

To a solution of β-lactam 25d (R⁹=butyl) (2.06 g, 11.1 mmol, 1 equiv) inTHF (150 mL) at 23° C. was added a solution of LiAlH₄ (1.0 M in THF,22.9 mL, 22.9 mmol, 2.06 equiv) via syringe over the course of 2 min.After stirring for 10 min at 0° C., the reaction was warmed to 23° C.,stirred for 15 min, and then refluxed for 3 h. The mixture was thencooled to 0° C. and quenched via careful addition of H₂O (1.0 mL),followed by 15% aqueous NaOH (1.0 mL), and then H₂O (2.5 mL). Theresulting suspension was stirred at 23° C. for 1.5 h, diluted with Et₂O(250 mL), and filtered through Celite, washing with Et₂O (250 mL). Thefiltrate was concentrated to furnish 1.42 g of the desired product 25e(R⁹=butyl) (9.93 mmol, 89%) as a clear oil. The product was used withoutfurther purification.

MS (ESPOS): 287.4 [2M+H]⁺.

To a solution of amino alcohol 25e (R⁹=butyl) (1.41 g, 9.86 mmol, 1equiv) in dichloromethane (50 mL) at 23° C. was added Boc₂O (2.59 g,11.9 mmol, 1.2 equiv). After stirring for 2 h at 23° C., the reactionmixture was concentrated. The product was purified via flash columnchromatography on silica gel using 33% EtOAc in hexane as eluent to give1.53 g (6.31 mmol, 64%) 25f (R⁹=butyl) as a clear oil.

MS (ESPOS): 266.0 [M+Na]⁺.

To a solution of NaIO₄ (8.81 g, 41.2 mmol, 10 equiv) in H₂O (60 mL) at23° C. was added RuCl₃.xH₂O (350 mg, catalytic amount) followed by asolution of alcohol 25f (R⁹=butyl) (1.00 g, 4.12 mmol, 1 equiv) inacetone (60 mL). The biphasic mixture was stirred for 30 min at 23° C.,then extracted with EtOAc (250 mL), decanting the organic layer. Theaqueous residue was extracted with two further portions of EtOAc (2×150mL). The combined organic extracts were treated with 2-propanol (75 mL)and stirred at 23° C. After stirring for 2 h the mixture was filteredthrough Celite, washing with EtOAc (300 mL). The filtrate wasconcentrated to furnish 0.78 g of the desired product 25 g (R⁹=butyl)(3.04 mmol, 74%) as a dark oil. The product was used without furtherpurification.

MS (ESPOS): 280.0 [M+Na]⁺.

Method X

To a solution of alcohol 25f (R^(9′)=2-methyl-2-butenyl) (3.31 g, 13.0mmol, 1 equiv) in DMF (100 mL) at 23° C. was added imidazole (2.21 g,32.5 mmol, 2.5 equiv) followed by TBSCl (2.93 g, 19.5 mmol, 1.5 equiv).The reaction was stirred for 35 min and then quenched with MeOH (2.0mL). After stirring for 5 min, the resulting mixture was partitionedbetween Et₂O (500 mL) and H₂O (400 mL). The organic layer was separatedand washed with H₂O (400 mL), brine (200 mL), dried (MgSO₄), filteredand concentrated to give 26a (R^(9′)=2-methyl-2-butenyl) 4.13 g (11.2mmol, 86%) of the desired product as a clear oil.

MS (ESPOS): 392.4 [M+Na]⁺.

A solution of intermediate 26a (R^(9′)=2-methyl-2-butenyl) (2.03 g, 5.50mmol, 1 equiv) in dichloromethane (80 mL) at −78° C. was treated withozone (1.2 L/min) introduced via a gas dispersion tube until a bluecolor was observed (20 min). A stream of oxygen (1.2 L/min) was thenpassed through the reaction mixture to discharge excess ozone. After 15min, oxygen flow was ceased and PPh₃ (2.16 g, 8.25 mmol, 1.5 equiv) wasadded. The reaction mixture was stirred at −78° C. for 30 min, then at0° C. for 15 min, and then warmed to 23° C. After stirring for 10 min at23° C., silica gel was added, and the resulting mixture concentrated todryness under vacuum to afford a free-flowing powder that was loadeddirectly onto a silica gel column. Flash column chromatography using30-33% EtOAc in hexane as eluent gave 1.52 g (4.42 mmol, 80%) ofaldehyde 26b as a clear oil.

MS (ESPOS): 398.0 [M+MeOH +Na]⁺.

To a suspension of cyclopropylmethyltriphenylphosphonium bromide (1.22g, 3.06 mmol, 1.5 equiv) in THF (10 mL) at 0° C. was added a solution ofNaHMDS (1.0 M in THF, 3.06 mL, 3.06 mmol, 1.5 equiv) dropwise viasyringe over the course of 1 min. The resulting solution was stirred for20 min at 0° C. then treated with a solution of aldehyde 26b (700 mg,2.04 mmol, 1 equiv) in THF (3.0 mL; 2×1.0 mL flush) transferred viacanula. After 15 min at 0° C. the reaction was warmed to 23° C., stirredfor a further 10 min then quenched with saturated NH₄Cl (30 mL). Theresulting mixture was partitioned between Et₂O (120 mL) and H₂O (50 mL).The organic layer was separated and washed with brine (50 mL), dried(MgSO₄) filtered and concentrated. Flash column chromatography using 10%EtOAc in hexane as eluent gave 588 mg (1.54 mmol, 76%) of 26c(R^(9′)=3-cyclopropyl-prop-3-enyl) as a clear oil.

MS (ESPOS): 404.3 [M+Na]⁺.

To a solution of alkene 26c (R^(9′)=3-cyclopropyl-prop-3-enyl) (191 mg,0.50 mmol, 1 equiv) in dioxane (5.0 mL) at 23° C. was added dipotassiumazodicarboxylate (973 mg, 5.01 mmol, 10 equiv) followed by slow additionof a solution of AcOH (573 μL, 10.0 mmol, 20 equiv) in dioxane (5.0 mL)over the course of 16 h via syringe pump. Following the completion ofthe addition the reaction was stirred a further 6 h then filteredthrough a glass frit with the aid of Et₂O (150 mL) to removeprecipitate. The resulting solution was washed with saturated aqueousNaHCO₃ (2×100 mL), brine (80 mL), dried (MgSO₄), filtered andconcentrated. The above procedure was repeated three times on the crudematerial obtained to give complete conversion of the alkene, providing183 mg (0.48 mmol, 96%) of the saturated product 26d(R⁹=3-cyclopropyl-propyl) as a clear oil.

MS (ESPOS): 406.0 [M+Na]⁺.

To a solution of TBS ether 26d (R^(9′)=3-cyclopropyl-propyl) (190 mg,0.50 mmol, 1 equiv) in THF (10 mL) at 23° C. was added a solution ofTBAF (1.0 M in THF, 0.55 mL, 0.55 mmol, 1.1 equiv). The resultingsolution was stirred for 40 min at 23° C. then partitioned between Et₂O(50 mL) and H₂O (50 mL). The organic layer was separated and washed withbrine (50 mL), dried (MgSO₄), filtered and concentrated to give 133 mg(0.50 mmol, 100%) of 26e (R⁹=3-cyclopropyl-propyl)as a clear oil.

MS (ESPOS): 290.2 [M+Na]⁺.

Catalytic Ruthenium oxidation of 26e to the desired carboxylic acidproduct 26f (R⁹=3-cyclopropyl-propyl) was conducted as described in theprevios examples.

MS (NEG): 282 [M−H]⁻.

Method Y

Synthesis of racemic 27a (R⁹=n-propyl). A solution of 10b (R⁹=n-propyl)(22 g, 0.13 mol) in methanol (30 mL) concentrated HCl (10 mL) was addedplatinum(IV)oxide (5 g). The reaction mixture was hydrogenated at 50 psifor 16 h, the catalyist was removed by filtration through celite® andthe filtrate evaporated to driness The crude pipecolic acid was usedwithout further purification.

The crude pipecolic acid residue 19 g was dissolved in acetonitrile (200mL), tetramethylammonium hydroxide.5H₂O (33 g) was added and thereaction mixture stirred 30 minuets, di-t-butyl pyrocarbonate (39 g,0.46 mol) was added and the reaction mixture stirred at room temperaturefor 72 h. Additional tetramethylammonium hydroxide.5H₂O (8 g) anddi-t-butyl pyrocarbonate (9 g) was added and the reaction mixturestirred 24h. The reaction solvent was remover invaccuo and the resultingoil was diluted with water (200 mL) and washed with ether (200 mL). Theaqueous portion was acidified to pH 3-4 with solid citric acid and thenextracted with ethyl acetate (3×200 mL). The combined organic layerswere dried over MgSO₄, filtered and the solvent removed to furnish 27a(R⁹=n-propyl) (19 g, 77%) as a yellow oil that crystallized on standing.

¹H NMR (300 MHz, CD₃OD) δ 4.31 (m, 1), 3.60 (m, 1), 3.33 (m, 1), 2.01(m, 4), 1.24 (m, 14), 0.89 (t, J=5.7, 3); MS (ESNEG): 270 [M−1]⁻.

The racemic a mixture 27a (R⁹=n-propyl) is diluted with acetonitrile (5volumes) and S-α-methylbenzyl amine (0.5 eq) the mixture is heated toreflux and allowed to cool with seeding. The mixture is allowed to standovernight. The first crop of salt formed is then filtered and put asideuntil the final recrystallisation.

The liquors from the filtration are concentrated in vacuo and then takenup in DCM (4 volumes), the DCM is then washed with 1 M citric acid (2/3volume of DCM). The DCM is then separated, dried over magnesium sulfate,filtered and concentrated in vacuo. The 2R, 4S enantiomer enriched freeacid is taken up in 5 volumes of acetonitrile and 0.85 eq. ofR-α-methylbenzyl amine was added and the mixture is heated to reflux andallowed to cool with seeding. The mixture is allowed to stand overnight.The salt formed is then filtered and put aside (the ee of the salt isgenerally 85-90%).

The process to obtain the second crop of 2S,4R salt is identical to thatof the previous paragraph except that the R-α-methylbenzyl amine isreplaced with S-α-methylbenzyl amine. The second crop salt formed isthen filtered (generally has an ee of around 80-90%) and put aside untilthe final recrystallisation.

The liquors from the filtration (2S,4R salt formation liquors, 2^(nd)crop) are concentrated in vacuo. The salt is broken by the methoddescribed previously. At this stage the impurities have beenconcentrated to such a level that salt formation is not possible. Thefree acid is subjected to column chromatography (30%EtOAc/Hexane) andthis removes the unwanted impurities. The column used a 10:1 weight toweight ratio of silica to compound. Also the compound was absorbed onto3 equivalents (wt:wt) of silica.

The free acid from the column (which is enriched with the 2R, 4Senantiomer) is diluted with acetonitrile (5 volumes) andR-α-methylbenzyl amine is added and the recrystalization repeaas

The salt break and formation of the 2S,4R salt is identical to thatdescribed previously. The third crop of salt formed generally has an eeof 80-90%.

The 3 crops of 2S,4R salt are combined and diluted with acetonitrile (7volumes). The mixture is heated to reflux at which point all the saltdissolves. The mixture is then allowed to cool to rt and stand overnightwith seeding. The salt that has precipitated out of solution isfiltered. The salt shows an ee of approximately 97%. The process isrepeated to give a salt with an ee of greater than 99%. The salt istaken up in DCM (4 volumes) and washed twice with 1M citric acid(approximately 2/3 volume of DCM) dried over magnesium sulfate, filteredand concentrated in vacuo. This process gives 77% of the theoreticalyield of the 2S,4R enantiomer. as an amber oil 98% ee.

Method Z

The conditions below are representative of the general coupling anddeprotection scheme depicted in method Z where P¹=H and P²=carboxylicacid-t-butyl ester (Boc).

To a solution of azetedine acid 25f (R⁹=butyl) (52 mg, 0.20 mmol, 1equiv), 7-Cl MTL 6b (R²=H, R³=Cl) (58 mg, 0.20 mmol, 1 equiv) and HBTU(84 mg, 0.22 mmol, 1.1 equiv) in DMF (2.0 mL) at 23° C. was added DIPEA(88 μL, 0.51 mmol, 2.5 equiv). After stirring for 12 h at 23° C., DMFwas removed in vacuo then the residue was partitioned between EtOAc (100mL) and 1:1 brine: 10% aqueous citric acid (100 mL). The organic layerwas separated and washed with 1:1 brine/saturated aqueous NaHCO₃ (100μL), brine (50 mL), dried (MgSO₄), filtered and concentrated to furnish82 mg (0.17 mmol, 84%) 13a (R²=H, R³=Cl, R⁹=butyl, P¹=H, P²=carboxylicacid-t-butyl ester, m=0) as a glassy solid which was used withoutpurification in the next step.

To a solution of carbamate 13a (R²=H, R³=Cl, R⁹=butyl, P¹=H,P²=carboxylic acid-t-butyl ester, m=0) (82 mg, 0.17 mmol, 1 equiv) in1,2-dichloroethane (10 mL) at 23° C. was added H₂O (0.40 mL) followed byTFA (4.0 mL). After stirring for 20 min at 23° C., toluene (50 mL) wasadded and the resulting solution was concentrated to dryness. Theresidue was purified by semi-preparative HPLC (Waters Nova-Pak® HR C₁₈,6 μm particle size, 60 Å pore size, 20 mm ID×100 mm, 5-60% acetonitrilein H₂O w/0.1% HCl over 30 min, 20 mL/min flow rate) to give 41 mg oftitle compound 3-Butyl-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amideas a white solid.

¹H NMR (300 MHz, CD₃OD) δ 5.30 (d, J=6.0 Hz, 1 H), 4.64 (d, J=7.8 Hz, 1H), 4.63-4.52 (m, 2 H), 4.29 (d, J=10.2 Hz, 1 H), 4.07 (dd, J=5.7, 10.2Hz, 1 H), 4.00 (t, J=6.6 Hz, 1 H), 3.82 (d, J=3.3 Hz, 1 H), 3.75 (dd,J=8.4, 9.9 Hz, 1 H), 3.56 (dd, J=3.3, 10.2 Hz, 1 H), 2.92-2.76 (m, 1 H),2.14 (s, 3 H), 1.90-1.67 (m, 2 H), 1.45 (d, J=6.6 Hz, 3 H), 1.44-1.24(m, 4 H), 0.93 (t, J=6.9 Hz, 3 H); MS (ESPOS): 411.0 [M+H]⁺.

Method AA

To pyridine-2-carboxylic acid 10b (0.5 mmol) in DMF (2 mL) lincosamineas defined in general coupling scheme 13 (0.5 mmol) was added, followedby HBTU (214 mg, 0.55 mmol) and DIEA (132 mg, 1 mmol). The reactionmixture is stirred at room temperature for 2 hr. The solvent wasremoved, and purification of the crude material was carried out bysilica gel column chromatography to obtain compound 13b

To a solution of the pyridine 13b (0.46 mmol) in water (10 mL), AcOH (3mL) and MeOH (2 mL), was added PtO₂ (200 mg) and the resulting reactionmixture shaken under 55 psi hydrogen overnight, or for an extendedperiod at lower hydrogen pressure. Residual catalyst was removed byfiltration through celite, and the solvent was removed to obtain thecrude product. Purification was carried out by silica gel columnchromatography using MeOH in DCM to obtain lincosamide analogs of type 1as defined in scheme 13.

In general silica chromatography readily separates the cis-2Sdiastereomer from the undesired isomer. In some cases separation of theisomers requires semi-preparative HPLC. A representative set ofconditions is as follows: (Waters Nova-Pak® HR C₁₈ column, 6 μm particlesize, 60 Å pore size, 20 mm ID×100 mm, 5-60% acetonitrile 0.1% AcOH/H₂O0.1% AcOH over 30 min, 20 mL/min flow rate.

Method AB

Synthesis of[2-Methyl-1-(3,4,5-tris-benzyloxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-carbamicacid tert-butyl ester, 15b step a (P₁=Boc, P₂=Bn, R²=Me, R³=H),(intermediate not shown). To a rapidly stirred solution of 2a (P=Boc,R¹=Me, R²=H) in benzene (40 mL) (2 g, 5.7 mmol) was added 50% aquiousKOH (12.8 mL) tetrabutylammonium bisulfate (0.67 g) and benzyl bromide(6.77 mL, 57.0 mmol) under N₂ atmosphere were suspended with vigorousstirring. After 3.5 h benzyl amine (6.0 mL) was added and the reactionmixture stirred an additional 20′ then toluene (300 mL) was added andthe organic layer washed, H₂O (2×100 mL), 2M KHSO₄ (3×100 mL), sat. aq.NaHCO₃ (1×100 mL), brine (1×100 mL) dried over MgSO₄ and evaporated todryness. Chromatography of the crude product on silica 10% EtOAc/Hexanesto 15% EtOAc/Hexanes product 15b, step a,2-Methyl-1-(3,4,5-tris-benzyloxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-carbamicacid tert-butyl ester as a colorless foam (2.6 g, 72%); MS (ESPOS):522.8 [M+H-Boc]⁺.

Synthesis of[2-Methyl-1-(3,4,5-tris-benzyloxy-6-fluoro-tetrahydro-pyran-2-yl)-propyl]-carbamicacid tert-butyl ester, 15b (P₁=Boc, P₂=Bn, R²=Me, R³=H), step b. To astirred solution cooled to −16° C. of the above intermediate2-Methyl-1-(3,4,5-tris-benzyloxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-carbamicacid tert-butyl ester (1.54 g, 2.5 mmol) in DCM (25 mL) was added DAST(0.599 mL, 4.46 mmol) under N₂ atmosphere were suspended with vigorousstirring. After 5 minutes solid NBS (0.599 mL, 4.46 mmol) was added over5 minuets and the reaction mixture stirred an additional 45′ then DCM(300 mL) was added and the organic layer washed with sat. aq. NaHCO₃(1×100 μL), dried over MgSO₄ and evaporated to dryness. Chromatographyof the crude product on silica 15% to 30% Et₂O/Hexanes product, amixture of 1-α and β Fluorinated[2-Methyl-1-(3,4,5-tris-benzyloxy-6-fluoro-tetrahydro-pyran-2-yl)-propyl]-carbamicacid tert-butyl ester 15b (P₁=Boc, P₂=Bn, R²=Me, R³=H), was isolated asa colorless oil (0.85 g, 58%); TLC (20% Et₂O/Hexanes) R_(f) isomer1=0.2, R_(f) isomer 1=0.05. ¹⁹F NMR (CDCl₃) δ isomer 1: −132.78,−132.96, isomer 2: −145.05, −145.13, −145.23, −145.31, HPLC C₁₈ 3.5 μm,4.6×30 mm Column; gradient eluent 2%-98% MeCN over 10 min; 1.5 mL/min):Retention time=7.93 min, 7.98 min; MS (ESPOS): 494.7 [M+H-Boc]⁺; MS(ESNEG): 592.7 [M−H]⁺.

Synthesis of2-Methyl-1-(6-allyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-yl)-propylamine,15c (P₁=H, P₂=Bn, R¹=Allyl, R²=Me, R³=H). To a stirred solution cooledto 32° C. of the above intermediate 15b (831 g, 2.5 mmol) in DCM (30 mL)under N₂ atmosphere was added allyltrimethylsilane (1.12 mL, 7.0 mmol).After 10 minutes BF₃.Et₂O (0.36 mL, 2.8 mmol) was added over 2 minuetsand the reaction mixture stirred an additional 1.5 h then then warmed to0° C. for 30 minuets. To the reaction mixture was added water (1 mL) andTFA (15 mL), the reaction mixture was allowed to warm to RT stirred 1 hand evaporated to driness. The residue was dissolved in Et₂O (200) mL)washed with 1M aq. K₂CO₃ (50 mL) and brine dried over Na₂SO₄ andevaporated to dryness the product 15c (P₁=H, P₂=Bn, R¹=Allyl, R²=Me,R³=H) was isolated as a colorless oil (0.69 g, 96%); TLC (20%EtOAc/Hexanes) R_(f)=0.05; MS (ESPOS): 516.4 [M+H-Boc]⁺.

2-(1-Amino-2-methyl-propyl)-6-propyl-tetrahydro-pyran-3,4,5-triol.2-Methyl-1-(6-allyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-yl)-propylamine,15c 160 mg and 100 mg degussa 50% w/w wet 10% palladium/carbon under N₂was suspended in THF (5 mL) and 1M aq. HCl (1 mL) the reaction mixturewas stirred 24 h under 1 atm pressure H₂. The reaction mixture wasfiltered through Celite evaporated to driness to provide the product2-(1-Amino-2-methyl-propyl)-6-propyl-tetrahydro-pyran-3,4,5-triol (60.8mg 89%) as the HCl salt. TLC (CHCl₃: MeOH: 32% aq. AcOH) R_(f)=0.35. MS(ESPOS): 248 [M+H]⁺.

Method AC

In general the final purification and separation of diastereoisomers ofcompounds detailed in the following examples may be achieved bysemi-preparative HPLC. Final products were purified on a Waters Prep LC4000® system equipped with a Waters 2487® dual λ absorbance detector setto 214 nm and a S.E.D.E.R.E Sedex 55® evaporative light scatteringdetector in series. General conditions used for the separation ofdiastereoisomers follows (Waters Nova-Pak® HR C₁₈ column, 6 μm particlesize, 60 Å pore size, 20 mm ID×100 mm, 5-60% acetonitrile 0.1% AcOH/H₂O0.1% AcOH over 30 min,20 mL/min flow rate. The fractions collected arepooled and lyophylized to driness.

EXAMPLES

The following examples were prepared according to the aforementionedmethods.

Example 1 4-(3,3-Difluoro-allyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-(3,3-Difluoro-allyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.To a solution of 2b (R^(2′)=H) (45 mg, 0.18 mmol, 1 equiv) in dry DMF(0.5 mL) at 0° C. was added triethylamine (79.4 μL, 0.57 mmol, 3.2equiv), followed by bis-(trimethylsilyl)trifluoroacetamide (71.2 μL,0.27 mmol, 1.5 equiv). The reaction mixture was stirred at 0° C. for 10minutes, and then was stirred at rt for 50 minutes. The reaction mixturewas added to the protected amino acid 8c (R⁹=3,3-difluoroallyl) preparedin general method M (56 mg, 0.19 mmol, 1.1 equiv) in a 25 mL roundbottom flask, followed by the addition of solid HATU (91.2 mg, 0.24mmol, 1.3 equiv). The reaction mixture was stirred at rt for 3 h. Thereaction mixture was evaporated to dryness, taken up in ethyl acetate(60 mL), washed with 10% citric acid (2×40 mL), water (40 μL), half sat.aq. NaHCO₃ (40 mL) and brine. The organic layer was dried over Na₂SO₄and evaporated to give a yellow syrup.

To a solution of the above crude coupling product in DCM (9 mL) withmethylsulfide (0.2 mL) were added trifluoroacetic acid (3 mL) and water(0.2 mL). The reaction mixture was stirred at rt for 1 h. The solventwas removed under vacuum and co-evaporated with toluene twice. Theresidue was purified by chromatography to provide the title compound4-(3,3-Difluoroallyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide(55.6 mg, 73%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.93 (br s,1), 5.30 (d, J=4.8, 1), 4.20-4.05 (m, 2), 3.96-3.77 (m, 3), 3.71-3.52(m, 2), 3.19-3.07 (m, 1), 2.78-2.63 (m, 1), 2.38-2.21 (m, 1), 2.13 (s,3), 2.20-1.97 (m, 4), 1.94-1.80 (m, 1), 0.92-0.84 (m, 6); MS (ESPOS):425.5 [M+H]⁺; MS (ESNEG): 423.5 [M−H]⁻.

Example 2 4-(3-Pyridin4-yl-allyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 2,4-(3-Pyridin-4-yl-allyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amidewas prepared according to the procedures described in Example 1 andgeneral Method M using the ylide derived fromtriphenyl(4-pyridylmethyl)phosphonum chloride in the wittig olefinationstep depicted in Scheme 8. HPLC: C₁₈ 3.5 μm, 4.6×30 mm column; gradienteluent 2%-98% MeCN over 10 min; 1.5 mL/min): R_(t)=2.99 min; MS (ESPOS):466.4 [M+H]⁺; MS (ESNEG): 464.2 [M−H]⁻, 500.3 [M+HCl]⁻.

Example 3 4-(3-Pyridin-4-yl-propyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 3,4-(3-Pyridin-4-yl-propyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amidewas prepared according to general Method M using the ylide derived fromtriphenyl(4-pyridylmethyl)phosphonum chloride in the wittig olefinationstep depicted in Scheme 8, followed by reductive deprotection toprotected aminoacid 8b (R⁹=3-pyridin-4-yl-propyl, R₂=H). The couplingand deprotection procedures described in Example 1 provided the desiredfinal product. HPLC: C₁₈ 3.5 μm, 4.6×30 mm column; gradient eluent2%-98% MeCN over 10 min; 1.5 mL/min): R_(t)=2.99 min; MS (ESPOS): 466.4[M+H]⁺; MS (ESNEG): 468.3 [M−H]⁻, 502.4 [M+HCl]−.

Example 4 4-Butylsulfanyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

N-Cbz-(2S),(4S)-(n-butylsulfanyl)proline 9d (P=Cbz, m=1,R9=n-butylsulfanyl). The title intermediate was prepared as described ingeneral method N. To a stirred solution of intermediate 9b (P=Cbz, m=1,LG=Ts) (1.34 g, 3.08 mmol) in DMF (10 mL), under N₂, was added,1-butanethiol (0.7 mL, 6.16 mmol, 2 equiv), followed by7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.7 mL, 4.87 mmol, 1.6equiv). After the addition, the resulting mixture was stirred at roomtemperature for 18 h, then partitioned between EtOAc and H₂O. Theorganic layer was separated, washed with brine, dried over Na₂SO₄,filtered and evaporated to dryness. The crude residue obtained waschromatographed on silica 3:1 hexanes/EtOAc to give methyl ester 9c(P=Cbz, m=1, R⁹=n-butylthio) (470 mg, 44%).

Methyl ester 9c was treated with lithium hydroxide (132.7 mg, 3.16 mmol,2.4 equiv) in 4:1 THF/H₂O, overnight. The pH of the reaction solutionwas adjusted to 3, with aq. 1 M HCl and extracted with EtOAc (3×100 mL).The combined organic phase was dried over Na₂SO₄, filtered, evaporatedto dryness, to provide the product 9dN-Cbz-(2S),(4S)-(n-butylthio)proline (463 mg, quant.).

To a suspension of MTL 1a (140 mg, 0.56 mmol, 1 equiv) in anhydrous DMF(2 mL), at 0° C. under N₂ was added triethylamine (0.3 mL, 2.2 mmol, 3.9equiv), followed by BSTFA (0.3 mL, 1.1 mmol, 2 equiv). The resultingmixture was stirred at 0° C. for 10 min, then at room temperature for 30mins, and cooled to 0° C. A solution of protected amino acidN-Cbz-(2S),(4S)-(n-butylthio)proline (215 mg, 0.64 mmol, 1.2 equiv) inanhydrous DMF (1 mL), was added, followed by solid HATU (320 mg, 0.84mmol, 1.5 equiv), cooling bath removed, and stirred at room temperaturefor 2 h. After evaporation of the reaction mixture under high vacuum,the residue obtained was diluted with ethyl acetate (150 mL), washedsequentially with 10% citric acid (2×50 mL), 0.5 M sat. aq. NaHCO₃ (2×50mL), brine (50 mL), dried over Na₂SO₄, filtered and evaporated todrynness. The per-silylated intermediate obtained was treated withDowex® 50w-400x H⁺ form resin (Aldrich)(200 mg) in MeOH (60 mL) for 45min, filtered, evaporated to dryness, chromatographed on silica (92:8DCM/methanol) to provide the desired Cbz protected lincosamide (185 mg,61%).

To a stirred suspension of 10% palladium on carbon (200 mg), inanhydrous EtOH (6 mL), under nitrogen, was added 1,4-cyclohexadiene (2mL), after 10 min, a solution of the above Cbz protected lincosamide(178 mg, 0.33 mmol) in EtOH (6 mL) was added. The resulting mixture wasstirred and heated to reflux overnight. After cooling, the reactionmixture was filtered through a celite pad, washed with ethanol, filtrateand washings evaporated to drynness. The crude residue obtained waschromatographed on silica (90:9:1 DCM/MeOH/conc. ammonium hydroxide) toprovide the title compound, which was taken up in 1:1 acetonitrile/water(4 mL), acidified (pH 4) with 1M HCl and lyophilized to provide the HClsalt (35 mg) as a colorless powder: MS (ESPOS): 439.3[M+H]+, 461.2[M+Na]+.

Example 5 4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 5 was prepared according to general MethodN using sodium ethanethiolate in the displacement step depicted inScheme 9. The coupling and deprotection procedures described in Example4 provided the desired final product. MS (ESPOS): 412.6 [M+H]⁺.

Example 6 4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 6 was prepared according to general methodN using triphenylphosphoniumdibromide to install a 4-(S) bromide leavinggroup in 9b (P=Cbz, m=1, LG=Br), sodium ethanethiolate was then used inthe displacement step depicted in Scheme 9. The coupling anddeprotection procedures described in Example 4 provided the desiredfinal product: MS (ESPOS): 411.6 [M]+.

Example 7 4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 7, was prepared according to generalmethod N using triphenylphosphoniumdibromide to install a 4-(S) bromideleaving group in 9b (P=Cbz, m=1, LG=Br), sodium ethanethiolate was thenused in the displacement step depicted in Scheme 9. The coupling anddeprotection procedures described in Example 4 provided the desiredfinal product: MS (ESPOS):. 429.1 [M+H]+; MS (ESNEG): 427.6 [M−H]⁻,463.6 [M+HCl]⁻.

Example 8 4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 8 was prepared according to general methodN, sodium ethanethiolate was then used in the displacement step depictedin Scheme 9. The coupling and deprotection procedures described inexample 4 provided the desired final product. MS (ESPOS): 429.1 [M+H]⁺.

Example 9 4-(4-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

To a solution of tosylate intermediate 14b (P=CF₃CO, m=1, R₂=H, R₃=OAc)prepared in general method R, scheme 14 (73.2 mg, 92 μmol) in dry DMF(300 μL) under N₂ was added 4-methylbenzylthiol (Lancaster) (63.5 μL,0.46 mmol), followed by MTBU (33.6 μL, 0.23 mmol). The reaction mixturewas stirred at rt 16 h. The reaction mixture was taken up in MeOH (1.5mL) 0.5 M NaOMe in MeOH (920 μL, 9.2 mmol) was added and the reactionmixture stirred at room temperature 18 h, then added to Dowex® resin bed(3.3 mL in water). The resin was washed with methanol (5×10 mL) water(1×10 mL) and acetonitrile (2×10 mL) the product was then eluted bywashed with 5% conc. NH₄OH in MeOH (5×10 mL) and MeCN (1×10 mL).Evaporation of the combined washes and prepartive TLC (95:5 MeOH:0.25MNH₃/DCM) to provide the title compound (25.0 mg, 56%) as a colorlesssolid: MS (ESPOS): 487.3 [M+H]⁺; HPLC: C₁₈ 3.5 μm, 4.6×30 mm column;gradient eluent 2%-98% MeCN over 5 min: R_(t)=1.91 min.

Example 10 4-(4-Fluoro-phenylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 10 was prepared by the procedure used inexample 9 from tosylate intermediate 14b (P=CF₃CO, m=1, R₂=H, R₃=OAc)prepared in general method R, scheme 14. 4-Fluorothiophenol (Aldrich)was the nucleophile used in the displacement step: MS (ESPOS): 477.3[M+H]⁺.

Example 11 4-(3,3,3-Trifluoro-propylsulfanyl)-pyrrolidine-2-carboxylicacid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 11 was prepared by the procedure used inexample 9 from tosylate intermediate 14b (P=CF₃CO, m=1, R₂=H, R₃=OAc)prepared in general method R, scheme 14. 1,1,1-trifluoropropanethiol(Aldrich) was the nucleophile used in the displacement step. (300 MHz,CDCl₃) δ 5.32 (d, J=5.8, 1), 4.43 (dd, J=8.2, 8.2 1), 4.36-4.31 (m, 1),4.19-4.04 (m, 3), 3.90-3.88 (m, 1), 3.78-3.55 (m, 3), 3.37-3.31 (m, 1),2.96-2.82 (m, 3), 2.61-2.49 (m, 2), 2.12 (s, 3), 2.07-2.01 (m, 2), 1.14(d, J=6.6, 3); (¹⁹F CDCl₃) δ −68.8 t; MS (ESPOS): 479.2 [M+H]⁺, 963.3[2M+H]⁺.

Example 12 4-(3-Methyl-butylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 12 was prepared by the procedure used inexample 9 from tosylate intermediate 14b (P=CF₃CO, m=1, R₂=H, R₃=OAc)prepared in general method R, scheme 14. 3-Methylbutanethiol (Aldrich)was the nucleophile used in the displacement step. MS (ESPOS): 453.3[M+H]⁺; HPLC: C₁₈ 3.5 μm, 4.6×30 mm column; gradient eluent 2%-98% MeCNover 10 min: R_(t)=3.90 min.

Example 13 4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 13 was prepared by the procedure used inexample 9 from tosylate intermediate 14b (P=CF₃CO, m=1, R₂=H, R₃=OAc)prepared in general method R, scheme 14. 2,4-Dichlorobenzyl thiol(Maybridge) was the nucleophile used in the displacement step: MS(ESPOS): 541.2 [M]⁺; HPLC: C₁₈ 3.5 μm, 4.6×30 mm column; gradient eluent2%-98% MeCN over 10 min: R_(t)=4.383 min.

Example 14 4-(Thiophen-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 14 was prepared by the procedure used inexample 9 from tosylate intermediate 14b (P=CF₃CO, m=1, R₂=H, R₃=OAc)prepared in general method R, scheme 14. Thiophen-2-yl methanethiol(Aldrich) was the nucleophile used in the displacement step: MS (ESPOS):479.2 [M+H]⁺; HPLC: C₁₈ 3.5 μm, 4.6×30 mm column; gradient eluent 2%-98%MeCN over 10 min: R_(t)=3.656 min.

Example 15 4-(Pyrazin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 15 was prepared by the procedure used inexample 9 from tosylate intermediate 14b (P=CF₃CO, m=1, R₂=H, R₃=OAc)prepared in general method R, scheme 14. 2-Mercaptomethyl pyrazine(Pyrazine Specialties Inc.) was the nucleophile used in the displacementstep. Purification of the title compound of example 15 was performed bypreparative TLC (16% methanolic ammonia/dichloromethane) gave theproduct (9 mg, 15%) of4-(Pyrazin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.MS (ESPOS): 475.5 [M+H]+; 497.4 [M+Na]+.

Example 16 4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

To a solution of 2b (R2′=H) (100 mg, 0.40 mmol, 1 equiv) in dry DMF (1mL) at 0° C. was added triethylamine (0.18 mL, 1.27 mmol, 3.2 equiv),followed by the addition of Bis(trimethylsilyl)trifluoroacetamide (0.16mL, 0.60 mmol, 1.5 equiv). The reaction mixture was stirred at 0° C. for10 minutes, and then was stirred at rt for 50 minutes. To the reactionmixture were added the Boc protected amino acid 9d (P=Boc, m=1,R9=2,4-dichlorobenzylsulfide) prepared in general method N (263 mg, 0.65mmol, 1.63 equiv), HATU (302 mg, 0.80 mmol, 2 equiv). The reactionmixture was stirred at rt for 3 h. The reaction mixture was evaporatedto dryness, taken up in ethyl acetate (150 mL), washed with 10% citricacid (2×80 mL), water (80 mL), half sat. NaHCO₃ (80 mL) and brine. Theorganic layer was dried over Na₂SO₄ and evaporated to give the desiredBoc protected lincosamide as a yellow syrup.

To a solution of the above Boc protected lincosamide in DCM (15 mL) withmethyl sulfide (0.33 mL) were added trifluoroacetic acid (5 mL) andwater (0.33 mL). The reaction mixture was stirred at rt for 1 h. Thesolvent was removed under vacuum and co-evaporated with toluene twice.The residue was purified by chromatography to provide a white solid (61mg). The white solid was purified by preparative thin layerchromatography to give4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide(47.5 mg, 22%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.84 (br s,1), 7.39-7.19 (m, 3), 5.31 (d, J=5.1, 1), 4.09 (dd, J=5.4, 9.9, 1),3.94-3.76 (m, 4), 3.81 (s, 2), 3.57-3.48 (m, 1), 3.40-3.32 (m, 1),3.22-3.14 (m, 1), 2.88-2.79 (m, 1), 2.64-2.54 (m, 1), 2.33-2.22 (m, 1),2.14 (s, 3), 1.93-1.85 (m, 1), 0.92-0.85 (m, 6). MS (ESPOS): 539.4[M+H]⁺.

Example 17 4-Butylsulfanyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

9c (P=Boc, m=1, R⁹=n-butylsulfide). To a solution of tosylate 9b (P=Boc,m=1) prepared in general method N (1.61 g, 4.03 mmol, 1 equiv) in dryDMF (12 mL) under N₂ was added n-butylthiol (1.30 mL, 12.1 mmol, 3equiv), followed by the addition of7-methyl-1,5,7-triazabicyclo-[4.4.0]dec-5-ene (MTBU) (0.87 mL, 6.05mmol, 1.5 equiv). The reaction mixture was stirred at rt overnight andconcentrated to dryness. The residue was taken up in ethyl acetate (100mL), washed with 10% citric acid (50 mL) and brine, and concentrated.The residue was purified by chromatography to provide a clear oil (1.24g, 97%): ¹H NMR (300 MHz, CDCl₃) δ 4.30 (t, J=8.0, 0.36), 4.23 (t,J=8.1, 0.64), 4.00-3.94 (m, 0.64), 3.87-3.82 (m, 0.36), 3.72 (s, 1.1),3.71 (s, 1.9), 3.29-3.15 (m, 2), 2.64-2.49 (m, 3), 1.97-1.84 (m, 1),1.60-1.32 (m, 4), 1.44 (s, 3.2), 1.38 (s, 5.8), 0.93-0.86 (m, 3).

9c (P=Boc, m=1, R9=n-butylsulfide). To a solution of methyl ester 9c(1.24 g, 3.91 mmol, 1 equiv) in THF (15 mL) and water (5 mL) was addedlithium hydroxide monohydrate (0.82 g, 19.55 mmol, 5 equiv). Thereaction mixture was stirred at rt overnight. THF was removed undervacuum. The residue was partitioned between ethyl acetate (200 mL) and10% citric acid (100 mL). The organic layer was washed with water (1×),brine (1×), dried over Na₂SO₄ and evaporated to give a clear oil 9c(P=Boc, m=1, R9=n-butyl) (1.21 g, 100%): MS (ESPOS): 204.4 [M-Boc+H]⁺,326.4 [M+Na]⁺; MS (ESNEG): 302.3 [M−H]⁻.

4-Butylsulfanyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.To a solution of 2b (R2′=H)(75 mg, 0.30 mmol, 1 equiv) in dry DMF (0.8mL) at 0° C. was added triethylamine (0.13 mL, 0.96 mmol, 3.2 equiv),followed by the addition of bis-(trimethylsilyl)trifluoroacetamide (0.12mL, 0.45 mmol, 1.5 equiv). The reaction mixture was stirred at 0° C. for10 minutes, and then was stirred at rt for 50 minutes. To the reactionmixture were added the Boc protected amino acid 9c (P=Boc, m=1,R9=n-Butylsulfide) (147 mg, 0.49 mmol, 1.63 equiv), HATU (227 mg, 0.60mmol, 2 equiv). The reaction mixture was stirred at rt for 3 h. Thereaction mixture was evaporated to dryness, taken up in ethyl acetate(100 mL), washed with 10% citric acid (2×60 mL), water (60 mL), halfsat. NaHCO₃ (60 mL) and brine. The organic layer was dried over Na₂SO₄and evaporated to give a yellow syrup.

To a solution of the above syrup in DCM (15 mL) with methyl sulfide(0.33 mL) were added trifluoroacetic acid (5 mL) and water (0.33 mL).The reaction mixture was stirred at rt for 1 h. The solvent was removedunder vacuum and co-evaporated with toluene twice. The residue waspurified by chromatography to provide a white solid,4-Butylsulfanyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide(95 mg, 73%): ¹H NMR (300 MHz, CD₃OD) δ 5.24 (d, J=6.0, 1), 4.14-4.02(m, 3), 3.94 (dd, J=7.1, 8.9, 1), 3.82 (d, J=3.3, 1), 3.51 (dd, J=3.3,10.2, 1), 3.45-3.32 (m, 2), 2.93 (dd, J=6.4, 10.6, 1), 2.71-2.55 (m, 3),2.23-2.13 (m, 1), 2.10 (s, 3), 1.83-1.72 (m, 1), 1.63-1.52 (m, 2),1.48-1.38 (m, 2), 0.97-0.88 (m, 9). MS (ESPOS): 437.5 [M+H]⁺.

Example 18 4-Azido-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

N-Boc-(2S,4R)-4-methanesulfonylproline methylester 9b (P=Boc, m=1,LG=Ms). To N-Boc-(2S,4R)-4-hydroxyproline methylester (Bachem) 9a(P=Boc, m=1), general method N (1 g, 4.0 mmol) in DCM (10 mL), pyridine(1.64 mL, 20.0 mmol), methanesulfonyl chloride (0.631 mL, 5.52 mmol) wasadded and let stirred for 2 hours at 0° C. and further stirred at roomtemperature overnight. More DCM (100 mL) was added, washed with HCl (1N,50 mL) and the organic portion was dried over magnesium sulfate. Themesylate product was obtained on removal of solvent (1.30 g, 100%) andused without further purification.

N-Boc-(2S,4S)-4-Azidoproline methylester 9c (P=Boc, m=1, R9=azide).N-Boc-(2S,4R)-4-methanesulfonylproline methylester was taken in DMF (10mL) to which sodium azide (1.30 g, 20.0 mmol) was added and heated at75-80° C. overnight. DMF was removed and the product was extracted withethyl acetate (100 mL) and washed with water (50 mL). The azide product9c (P=Boc, m=1, R9=azide) was obtained (0.98 g, 90%) on removal ofsolvent.

9d (P=Boc, m=1, R9=azide). A stirred solution of 9c (P=Boc, m=1,R9=azide) in THF (10 mL) was treated with lithium hydroxide (300 mg,7.14 mmol) in water (0.5 mL) overnight. The excess solvent was removedby rotary evaporation and the residue was extracted with ethyl acetateand discarded. The aqueous portion was acidified, extracted with ethylacetate and dried over magnesium sulfate. Removal of solvent resulted inthe protected amino acid N-Boc-(2S,4S)-4-azidoproline 9d (P=Boc, m=1,R9=azide)(0.8 g, 88%): ¹H NMR (300 MHz, CD₃OD) δ 4.34-4.24 (m, 2),3.73-3.64 (m, 1), 3.39-3.34 (m, 1), 2.61-2.51 (m, 1), 2.16-2.09 (m, 1),1.46 (s, 3), 1.42 (s, 6); MS (ESNEG): 255 (M−1).

1-(2-(S)-4-(S)-(Azido)-N-pyrrolidin-2-yl-{1-(R)-[2-(S),3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide.To 2b (R9′=H) (200 mg, 0.788 mmol) in DMF (5 mL) at 0° C., triethylamine(0.164 mL, 1.18 mmol) and bis-(trimethylsilyl)trifluoroacetamide (0.93mL, 3.94 mmol) were added and then left stirring at room temperatureovernight. After which, N-Boc-(2S,4S)-4-azidoproline (300 mg, 1.18 mmol)and HATU (444 mg, 1.18 mmol) was added at 0° C. and then left stirringfor four hours. At the end, DMF was removed and the residue was taken inethyl acetate (100 mL) and washed with citric acid (10%, 30 mL),saturated sodium bicarbonate (30 mL) and brine (30 mL). After drying theorganic portion with sodium sulfate, the solvent was removed to obtainthe crude product which was taken as such for the next deprotectionstep. To the crude product in dichloroethane 30% trifluoroacetic acid(10 mL) and dimethylsulfide (0.5 mL) was added and the reaction mixturewas stirred for an hour. The solvent was removed and the crude productobtained was chromatographed on silica gel column using 20% methanol inDCM to obtain the title compound as a white solid (278 mg, 90%): TLC:R_(f)=0.38 (40% methanol in DCM); ¹H NMR (300 MHz, CD₃OD) δ 4.24 (d,J=5.4, 1), 4.16 (s, 1), 4.03-4.13 (m, 3), 3.95 (d, J=3.6, 1), 3.80 (dd,J=4.5, 9.9, 1), 3.51-3.56 (dd, J=3.3, 10.2, 1), 3.13-3.22 (m, 1),2.95-3.00 (m, 1), 2.35-2.45 (m, 1), 2.08 (s, 3), 1.93-2.04 (m, 1), 1.29(t, J=7.2, 1), 0.97 (m, 3); MS (ESPOS): 392 [M+H]+.

Example 194-[3-(Furan-2-ylmethylsulfanyl)-prop-1-yl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-(3-Hydroxy-propyl)-2-[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester

To a mixture of 2b (R^(2′)=H) (532 mg, 1.85 mmol, 1 equiv) in dry DMF(4.5 mL) at 0° C. was added triethylamine (1.28 mL, 9.25 mmol, 5 equiv),followed by the addition of Bis-(trimethylsilyl)trifluoroacetamide (0.74mL, 2.78 mmol, 1.5 equiv). The reaction mixture was stirred at 0° C. for10 minutes, and then was stirred at rt for 50 minutes. To the reactionmixture were added the Boc protected amino acid 11f(R^(9′)=3-t-butyldimethylsiloxypropyl, P=Boc) prepared in general methodP (741 mg, 1.85 mmol, 1.0 equiv) and HATU (886 mg, 2.33 mmol, 1.26equiv). The reaction mixture was stirred at rt for 3 h. The reactionmixture was evaporated to dryness, taken up in ethyl acetate, washedwith 10% citric acid (1×), water (1×), sat. NaHCO₃ (1×) and brine. Theorganic layer was dried over Na₂SO₄ and concentrated to give a yellowsyrup. The residue was taken up into methanol (20 mL) and followed bythe addition of Dowex® resin (340 mg). The mixture was stirred at rt for1 hr and the resin was removed by filtration. The filtrate wasconcentrated and the residue was purified by column chromatography togive the product4-(3-hydroxy-propyl)-2-[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (694 mg, 72%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 5.33-5.28 (m, 1), 4.16-3.97 (m, 3), 3.89-3.69 (m, 3), 3.65-3.58(m, 2), 3.56-3.47 (m, 1), 3.17-3.06 (m, 1), 2.33-2.23 (m, 1), 2.14 (s,1.5), 2.13 (s, 1.5), 1.94-1.80 (m, 2), 1.67-1.50 (m, 5), 1.45 (s, 9),1.42-1.23 (m, 2), 0.93-0.82 (m, 6). MS (ESPOS): 521.7 [M+H]⁺.

2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-[3-(toluene-4-sulfonyloxy)-propyl]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-(3-Hydroxy-propyl)-2-[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (196 mg, 0.38 mmol, 1 equiv) and p-toluenesulfonicanhydride (123 mg, 0.38 mmol, 1 equiv) in DCM (1.5 mL) at 0° C. wasadded dropwise triethylamine (63 μL, 0.45 mmol, 1.2 equiv). The reactionmixture was stirred at 0° C. for 5 hr then diluted with ethyl acetate.The organic layer was washed with sat. sodium bicarbonate, brine, driedand concentrated to give a white solid which was purified bychromatography to give 11h (147.5 mg, 58%) as a white solid; ¹H NMR (300MHz, CDCl₃) δ 7.78-7.74 (m, 2), 7.35-7.31 (m, 2), 5.30 (d, J=5.7, 1),4.13-4.06 (m, 1), 4.03-3.93 (m, 3), 3.91-3.60 (m, 4), 3.54-3.45 (m,1),3.12-3.02 (m, 1), 2.43 (s, 3), 2.32-2.21 (m, 1), 2.121 (s, 1.7), 2.117(s, 1.3), 1.83-1.73 (m, 2), 1.65-1.59 (m, 4), 1.45 (s, 5), 1.44 (s, 4),1.37-1.15 (m, 3), 0.93-0.81 (m, 6); MS(ESPOS): 675.9 [M+H]⁺.

4-[3-(Furan-2-ylmethylsulfanyl)-propyl]-2-[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of Boc protected tosylate2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-[3-(toluene-4-sulfonyloxy)-propyl]-piperidine-1-carboxylicacid tert-butyl ester (91 mg, 0.13 mmol, 1 equiv) in dry DMF (0.42 mL)under N₂ was added furfuryl mercaptan (68 μL, 0.67 mmol, 5 equiv),followed by the addition of7-methyl-1,5,7-triazabicyclo-[4.4.0]dec-5-ene (MTBU) (48 μL, 0.33 mmol,2.5 equiv). The reaction mixture was stirred at rt overnight and dilutedwith DCM, washed with brine (3×), dried and to concentrated. The residuewas purified by preparative TLC (8% MeOH/DCM) to provide the desired Bocprotected thioether4-[3-(Furan-2-ylmethylsulfanyl)-propyl]-2-[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (63.3 mg, 76%) as a clear syrup: MS (ESPOS): 617.9[M+H]⁺.

To a solution of the Boc protected thioether4-[3-(Furan-2-ylmethylsulfanyl)-propyl]-2-[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester in DCM (9 mL) with methyl sulfide (0.2 mL) wereadded trifluoroacetic acid (3 mL) and water (0.2 mL). The reactionmixture was stirred at rt for 1 h. The solvent was removed under vacuumand co-evaporated with toluene twice. The residue was purified bypreparative TLC to provide the title lincosamide product for example 19(13 mg, 25%) as a white solid; ¹H NMR (300 MHz, CD₃OD) δ 7.39 (dd,J=0.8, 2.0, 1), 6.32 (dd, J=2.1, 3.3, 1), 6.18 (dd, J=0.8, 3.2, 1), 5.24(d, J=5.7, 1), 4.17 (dd, J=3.2, 10.1, 1), 4.10-4.02 (m, 2), 3.79 (d,J=3.3, 1), 3.71 (s, 2), 3.50 (dd, J=3.3, 10.2, 1), 3.43 (dd, J=2.9,11.9, 1), 3.24-3.17 (m, 1), 2.78-2.67 (m, 1), 2.49 (t, J=7.1, 2),2.20-2.11 (m, 1), 2.10 (s, 3), 2.06-1.93 (m, 1), 1.78-1.70 (m, 1),1.62-1.52 (m, 3), 1.38-1.29 (m, 2), 1.20-1.06 (m, 2), 0.91 (d, J=7.2,6); MS(ESPOS): 517.8 [M+H]⁺.

Example 20 4-(3-Imidazol-1-yl-prop-1-yl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-(3-Imidazol-1-yl-prop-1-yl)-2-[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester. To a mixture of NaH (60%, 11.9 mg, 0.30 mmol, 2equiv) in dry DMF (0.2 mL) at 0° C. was added a solution of imidazole(40.4 mg, 0.60 mmol, 4 equiv) in DMF (0.25 mL) dropwise. The mixture wasstirred at 0° C. for 10 min, then was cooled to −78° C. To the mixturewas added a solution of Boc protected tosylate prepared in example 19(100 mg, 0.15 mmol, 1 equiv) in dry DMF (0.4 mL) dropwise. The mixturewas stirred at 0° C. for 2 hr, then at rt overnight. The reactionmixture was diluted DCM, washed with brine (3×), dried and concentrated.The residue was purified by chromatography to give the title Bocprotected imidazole compound (60 mg, 71%) as a white solid. MS (ESPOS):571.8 [M+H]⁺.

To a solution of the above Boc protected imidazole in DCM (9 mL) withmethyl sulfide (0.2 mL) were added trifluoroacetic acid (3 mL) and water(0.2 mL). The reaction mixture was stirred at rt for 1 h. The solventwas removed under vacuum and co-evaporated with toluene twice. Theresidue was purified by chromatography to provide the title lincosamidecompound for example 2Q (10 mg, 20%) as a white solid: ¹H NMR (300 MHz,CD₃OD) δ 7.63 (s, 1), 7.11 (s, 1), 6.95 (s, 1), 5.23 (d, J=5.7, 1), 4.14(dd, J=3.2, 10.1, 1), 4.10-3.99 (m, 4), 3.79 (d, J=3.6, 1), 3.50 (dd,J=3.3, 10.2, 1), 3.27-3.21 (m, 1), 3.14-3.07 (m, 1), 2.64-2.54 (m, 1),2.19-2.10 (m, 1), 2.10 (s, 3), 1.94-1.76 (m, 3), 1.70-1.64 (m, 1),1.55-1.43 (m, 1), 1.30-1.18 (m, 2), 1.11-0.94 (m, 2), 0.92-0.88 (m, 6);MS (ESPOS): 471.7 [M+H]⁺.

Example 214-[3-(Thiophen-2-ylsulfanyl)-prop-1-yl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-[3-(Thiophen-2-ylsulfanyl)-prop-1-yl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.To a solution of protected tosylate prepared in example 19 (97 mg, 0.14mmol, 1 equiv) in dry DMF (0.42 mL) under N₂ was added 2-thienylmercaptan (Acros) (68 μL, 0.72 mmol, 5 equiv), followed by the additionof 7-methyl-1,5,7-triazabicyclo-[4.4.0]dec-5-ene (MTBU) (51.3 μL, 0.36mmol, 2.5 equiv). The reaction mixture was stirred at rt overnight anddiluted with DCM, washed with brine (3×), dried and concentrated. Theresidue was purified by preparative TLC (8% MeOH/DCM) to provide a clearsyrup (65.5 mg, 74%): MS (ESPOS): 619.8 [M+H]⁺.

To a solution of the above syrup in DCM (9 mL) with methyl sulfide (0.2mL) were added trifluoroacetic acid (3 mL) and water (0.2 mL). Thereaction mixture was stirred at rt for 1 h. The solvent was removedunder vacuum and co-evaporated with toluene twice. The residue waspurified by preparative TLC to provide the title lincosamide compoundfor example 21 (16 mg, 29%) as a white solid; ¹H NMR (300 MHz, CD₃OD) δ7.45-7.42 (m, 1), 7.12-7.09 (m, 1), 7.01-6.96 (m, 1), 5.23 (d, J=5.7,1), 4.16 (dd, J=3.3, 10.2, 1), 4.10-4.01 (m, 2), 3.79 (d, J=3.3, 1),3.50 (dd, J=3.3, 10.5, 1), 3.34-3.28 (m, 1), 3.18-3.10 (m, 1), 2.76 (t,J=7.1, 2), 2.68-2.58 (m, 1), 2.20-2.06 (m, 1), 2.10 (s, 3), 1.98-1.88(m, 1), 1.71-1.28 (m, 6), 1.13-1.00 (m, 2), 0.90 (d, J=6.9, 6); MS(ESPOS): 519.7 [M+H]⁺.

Example 22 4-(3-Ethylsulfanyl-prop-1-yl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 22 was prepared from protected tosylateintermediate prepared in example 19, according to the procedure used inexamples 19-21, using sodium ethanethiolate in the displacement step; MS(ESPOS): 465.3 [M+H]⁺.

Example 23 4-(3-Cyano-prop-1-yl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound of example 23 was prepared from protected tosylateintermediate prepared in example 19, 11h according to the procedure usedin examples 19-21 using sodium cyanide nucleophile in the displacementstep; MS (ESPOS): 430.3 [M+H]⁺.

Example 244-(3-Difluoromethylsulfanyl-prop-1-yl)-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

11c (R^(9′)=3-hydroxy-propyne).

To a mixture of 4-iodopicolinic acid methyl ester 11b (4.36 g, 16.5mmol, 1 equiv), triphenylphosphine (346 mg, 1.32 mmol, 0.08 equiv),copper iodide (251 mg, 1.32 mmol, 0.08 equiv), palladium acetate (148mg, 0.66 mmol, 0.04 equiv) in triethylamine (60 mL) at 23° C. was addedpropargyl alcohol (1.92 mL, 33.0 mmol, 2 equiv), and the reactionmixture was stirred at 23° C. overnight. The reaction mixture wasconcentrated under high vacuum and the black residue was purified bycolumn chromatography (2% MeOH in methylene chloride) to yield a brownoil. The brown oil was purified again by column chromatography (100%EtOAc) to yield the desired product, 11c (R^(9′)=3-hydroxy-1-propyne) asa yellow oil (3.0 g, 95%): ¹H NMR (300 MHz, CDCl₃) 8.70-8.74 (dd, J=0.9,5.1, 1), 8.14 (s,l), 7.46-7.50 (dd, J=1.8, 5.1, 1), 4.54 (d, J=6.3, 2),4.02 (s, 3); MS (ESPOS): 192.1 [M+H]; 214.1 [M+Na]; HPLC: (Symmetry C183.5 μm, 4.6 30 mm Column; gradient eluent 2%-98% MeCN over 5 min; 1.5mL/min): Rt=1.42 min.

11c (R^(9′)=3-hydroxy-propyl).

To a solution of 11c (R9′=3-hydroxy-1-propyne) (2.0 g, 10.5 mmol, 1.0equiv) in MeOH (120 mL) at 23° C. was added 20 wt. % Pd(OH)2 on carbon(1.0 g) and the reaction mixture was stirred under hydrogen atmosphereovernight. The reaction mixture was filtered through celite and thefiltrate was concentrated to yield the desired product,4-(3-hydroxy-propyl)-pyridine-2-carboxylic acid methyl ester 11c(R^(9′)=3-hydroxy-propyl) (2.03 g, 99%) as yellow oil: ¹H NMR (300 MHz,CDCl₃) 8.65 (d, J=5.1, 1), 8.03 (s, 1), 7.34-7.36 (dd, J=1.8, 5.1, 1),4.02 (s, 3), 3.71 (t, J=6.0, 12.3, 2), 2.83 (t, J=7.8, 15.6, 2),1.92-1.97 (m, 2); MS (ESPOS): 196.3 [M+H] MS (ESNEG): 194.2 [M−H]; HPLC:(Symmetry C18 3.5 μm, 4.6 30 mm Column; gradient eluent 2%-98% MeCN over5 min; 1.5 mL/min): Rt=1.46 min.

11d (R^(9′)=3-hydroxy-propyl).

To a solution of 4-(3-Hydroxy-propyl)-pyridine-2-carboxylic acid methylester, 11c (R^(9′)=1-hydroxypropyl) (1.81 g, 9.28 mmol, 1.0 equiv) inMeOH (30 mL) and H₂O (20 mL) at 23° C. was added concentrated HCl (412L, 11.1 mmol, 1.2 equiv), followed by platinum(IV) oxide (600 mg, 0.33wt %) and the reaction mixture was stirred vigorously under hydrogenatmosphere at 1 atm for 48 h. The reaction mixture was filtered throughcelite washing with methanol (200 mL). The combined filtrate wasconcentrated under reduced pressure to yield the desired product 11d,R^(9′)=(3-hydroxy-propyl) as an HCl salt (2.02 g, 8.52 mmol, 91%): MS(ESPOS): 202.2 [M+H]+.

11e (R^(9′)=3-hydroxy-propyl, P=Cbz).

To a solution of 11d, R^(9′)=(3-hydroxy-propyl) (2.02 g, 8.52 mmol, 1equiv) in dichloromethane (50 mL) at 5° C. was added triethylamine (1.54mL, 11.07 mmol, 1.3 equiv), and the reaction mixture was stirred for 10min. To this solution was added benzylchloroforrnate (1.55 mL, 11.07mmol, 1.3 equiv) and the reaction mixture was stirred at 5° C. for 1 h,then warmed to room temperature. The reaction mixture. was concentrated,and the crude product was partitioned between dichloromethane (250 mL)and water (150 mL). The organic layer was collected, dried over Na2SO4,and concentrated. The residue was purified by column chromatography(gradient from 50% to 75% EtOAc/hexane) to yield the desired product,11e (R^(9′)=3-hydroxy-propyl, P=Cbz) (2.28 g, 6.80 mmol, 80%) as ayellow oil: ¹H NMR (300 MHz, CDCl₃) 7.34 (s, 5), 5.19 (s, 2), 4.48 (t,J=6.3, 12.3, 1), 3.68 (bs, 3), 3.60-3.64 (m, 2), 3.38-3.42 (m, 2),1.94-1.98 (m, 3), 1.65-1.80 (m, 2), 1.33-1.37 (m, 2), 1.20-1.24 (m, 2);MS (ESPOS): 358.0 [M+Na]; HPLC: (Symmetry C18 3.5 μm, 4.6 30 mm Column;gradient eluent 2%-98% MeCN over 5 min; 1.5 mL/min): Rt=2.50 min.

11e (R^(9′)=3-methanesulfonylpropyl, P=Cbz)

To a solution of alcohol intermediate 11e (R^(9′)=3-hydroxy-propyl,P=Cbz) prepared by general method P (2.0 g, 5.97 mmol, 1 equiv) indichloromethane (15 mL) at 0° C. was added triethylamine (1.0 mL 7.2mmol, 1.2 equiv), and the reaction mixture was stirred for 15 min. Tothis solution was added methanesulfonic anhydride (1.04 g, 5.97 mmol, 1equiv), and the reaction mixture was stirred for a further 30 min at 0°C. The reaction mixture was partitioned between dichloromethane (250 mL)and saturated aqueous NaHCO₃ (100 mL). The organic layer was collected,dried over Na₂SO₄, and concentrated to yield the desired mesylateproduct 11e (R^(9′)=3-methanesulfonylpropyl, P=Cbz) (2.25 g, 5.45 mmol,91%) as clear oil: ¹H NMR (300 MHz, CDCl₃) δ 7.34 (s, 5), 5.19 (s, 2),4.48 (t, J=6.3, 12.3, 1), 4.20 (t, J=6.3, 14.1, 2), 3.70 (bs, 3),3.38-3.42 (m, 2), 3.02 (s, 3), 1.94-1.98 (m, 3), 1.65-1.80 (m, 2),1.33-1.37 (m, 2), 1.20-1.24 (m, 2); MS (ESPOS): 436.3 [M+Na]; HPLC(Symmetry ® C₁₈ 3.5 μm, 4.6×30 mm Column; gradient eluent 2%-98% MeCNover 5 min; 1.5 mL/min): R_(t)=2.86 min.

11e (R^(9′)=3-acetylsulfanyl-propyl, P=Cbz)

To a solution of mesylate 11e (R^(9′)=3-methanesulfonylpropyl, P=Cbz)(2.25 g, 5.45 mmol, 1 equiv) in DMF (30 mL) at 5° C. was added potassiumthioacetate (3.11 g, 27.3 mmol, 5 equiv) and the reaction mixture wasstirred at 5° C. overnight. The reaction mixture was partitioned betweenEtOAc (250 mL) and saturated aq. NaHCO₃ (100 mL). The organic layer wascollected, dried over Na₂SO₄, and concentrated. The crude productobtained was purified by column chromatography (25% EtOAc in hexane) toyield the desired thioester product 11e (R^(9′)=3-acetylsulfanyl-propyl,P=Cbz) (1.90 g, 4.83 mmol, 89%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃)δ 7.34 (s, 5), 5.12 (s, 2), 4.46 (t, J=6.3, 12.3, 1), 3.69 (bs, 3),3.38-3.42 (m, 2), 2.81-2.85 (m, 3), 2.32 (s, 3), 1.89-2.05 (m, 3),1.65-1.80 (m, 2), 1.33-1.37 (m, 2), 1.20-1.24 (m, 2); MS (ESPOS): 394.0[M+H] 416.1 [M+Na]; HPLC (Symmetry ® C₁₈ 3.5 μm, 4.6×30 mm Column;gradient eluent 2%-98% MeCN over 5 min; 1.5 mL/min): Retention time=3.28min.

11f (R^(9′)=3-Difluoromethylsulfanyl-propyl, P=Cbz).

To a solution of 11e (R^(9′)=(3-acetylsulfanyl-propyl), P=Cbz) (1.90 g,4.83 mmol, 1 equiv) in ethanol (8 mL) was added 3 N NaOH (4.5 mL). Thereaction mixture was stirred at room temperature for 45 min, thenconcentrated to give a clear oil. The resulting oil was dissolved inethanol (20 mL) and the reaction mixture was de-oxygenated viaevacuation of the reaction flask, then the reaction mixture wassaturated with chlorodifluoromethane gas (Aldrich) at 1 atm. pressure.The reaction mixture was stirred at 5° C. for 16 h, then neutralizedwith 1 N HCl at 0° C., and concentrated under reduced pressure. Theresidue was made basic with 0.5 N aqueous NaOH and washed with ether.The aqueous layer was acidified to pH 2.0 with 1N HCl, and extractedwith ethyl acetate (3×100 mL). The organic layer was washed with brine(2×100 mL), dried (MgSO₄), and concentrated. The crude residue obtainedwas purified by column chromatography (50% EtOAc/49% Hexane/1% AcOH) toyield the desired difluoromethyl sulfide product 11f(R^(9′)=(3-difluoromethylsulfanyl-propyl), P=Cbz) (0.75 g, 1.94 mmol,40%) as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 7.36 (s, 5), 6.97 (s),6.79 (s), 6.60 (s), 5.15 (s, 2), 4.51 (t, J=6.3, 12.3, 1), 3.38-3.42 (m,2), 2.75 (t, J=7.2,14.4, 1), 2.47-2.51 (m, 1), 1.89-2.05 (m, 3),1.65-1.80 (m, 2), 1.33-1.37 (m, 2), 1.21-1.23 (m, 2); MS (ESPOS): 388.1[M+H]+ 410.1 [M+Na]+; HPLC (Symmetry ® C₁₈ 3.5 μm, 4.6×30 mm Column;gradient eluent 2%-98% MeCN over 5 min; 1.5 mL/min): Rt=2.85 min.

11f (R^(9′)=3-difluoromethylsulfanyl-propyl, P=Boc).

To a solution of (750 mg, 1.94 mmol, 1 equiv) in acetonitrile (100 mL)at 23° C. was added iodotrimethylsilane (0.8 mL, 5.81 mmol, 3 equiv),and the reaction mixture was stirred for 30 min. The reaction mixturewas concentrated to yield the deprotected crude product (491 mg, 1.94mmol, 100%). To this was added dichloromethane (100 mL), triethylamine(0.54 mL, 3.88 mmol, 2 equiv), and di-tert-butyl dicarbonate (0.67 mL,2.91 mmol, 1.5 equiv). The reaction mixture was stirred at 5° C.overnight. The reaction mixture was concentrated, and the crude productwas partitioned between dichloromethane (250 mL) and water (150 mL). Theorganic layer was collected, dried (Na₂SO₄), and concentrated. The cruderesidue obtained was purified by column chromatography (50:49:1EtOAc/hexane/AcOH) to yield the desired product 11f(R^(9′)=3-difluoromethylsulfanyl-propyl, P=Boc) (671 mg, 98%) as a clearoil: ¹H NMR (300 MHz, CD₃OD) δ 7.10 (s), 6.90 (s), 6.70 (s), 4.19-4.23(m, 1), 3.48-3.53 (m, 1), 2.68 (t, J=6.6, 13.8,1), 2.56 (t, J=7.2, 14.4,1), 1.80-1.95 (m, 4), 1.50-1.80 (m, 5), 1.33 (s, 9), 1.13-1.20 (m, 2);MS (ESPOS): 254.1 [M-Boc+H] MS (ESNEG): 352.2 [M−H]−.

4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

To a stirred solution of 7-Cl-MTL 6b (R²=H, R³=Cl) (195 mg, 0.68 mmol,1.2 equiv) in DMF (2.5 mL) at 23° C. was added diisopropylethylamine(0.3 mL, 1.71 mmol, 3 equiv), followed by a solution of boc protectedamino acid 11f (R9′=3-difluoromethylsulfanyl-propyl, P=Boc) (200 mg,0.57 mmol, 1 equiv) in DMF (2.5 mL), and HBTU (324 mg, 0.85 mmol, 1.5equiv). The resulting solution was stirred at room temperature for 3 h,then concentrated to dryness. The solid residue was partitioned betweenethyl acetate (300 mL) and saturated aq. NaHCO₃ (100 mL). The organiclayer was collected, dried (Na₂SO₄) and concentrated. To a portion ofthis residue (60 mg, 0.12 mmol, 1 equiv) at 23° C. was added1,2-dichloroethane (5 mL), water (0.2 mL) followed by neat TFA (2.0 mL),and the reaction mixture was stirred for 15 min at room temperature,then concentrated in vacuo. The crude product was purified bypreparative HPLC to yield the title compound for example 24 as a whitepowder: ¹H NMR (300 MHz, CD₃OD) δ 7.12 (s), 6.93 (s), 6.74 (s), 5.21 (d,J=5.7, 1), 4.48 (d, J=8.4, 2) 4.40 (d, J=10.2, 1), 4.17 (d, J=9.6, 1),3.97-4.02 (dd, J=5.4, 9.9, 1) 3.71 (d, J=3.3), 3.46-3.52 (m, 2),2.71-2.76 (t, J=6.9, 13.8, 1), 2.05 (s, 3), 1.83 (s, 1), 1.61-1.77 (m,5), 1.35 (d,J=6.9, 4), 1.08-1.22 (m, 3); MS (ESPOS): 507.1 [M+H]⁺.

Example 25 4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.To a stirred solution of 2b (R2′=H) in DMF (2.5 mL) at 23° C. was addeddiisopropylethylamine (0.3 mL, 1.7 mmol, 3 equiv), followed by asolution of Boc protected amino acid 11f(R9′=3-difluoromethylsulfanyl-propyl, P=Boc) (200 mg, 0.57 mmol, 1equiv) in DMF (2.5 mL), and HBTU. The resulting solution was stirred atroom temperature for 3 h, and concentrated to dryness. The solid residuewas partitioned between ethyl acetate (300 mL) and saturated aq. NaHCO₃.The organic layer was collected, dried (Na₂SO₄) and concentrated. To aportion of this residue (60 mg, 0.12 mmol, 1 equiv) at 23° C. was added1,2-dichloroethane (5 mL), water (0.2 mL) followed by neat TFA (2.0 mL),and the reaction mixture was stirred for 15 min at room temperature,then was concentrated. The crude product was purified by preparativeHPLC to yield the desired title compound for example 25 as a whitepowder: ¹H NMR (300 MHz, CD₃OD) δ 7.13 (s), 6.94 (s), 6.75 (s), 5.16 (d,J=5.7, 1), 4.12 (d, J=9.9, 1), 3.97-4.02 (dd, J=4.8, 10.2, 2), 3.71 (d,J=3.3, 1), 3.42-3.46 (m, 2), 2.88-2.96 (m, 2), 2.75 (t, J=7.8, 15.0, 2),2.59-2.63 (m, 2), 2.03 (s, 3), 1.81-1.87 (m, 1), 1.61-1.70 (m, 5),1.20-1.38 (m, 4), 0.82-0.84 (d, J=6.9, 6); MS (ESPOS): 487.1 [M+H]⁺.

Example 26 4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-(3,3-Diethoxy-prop-1-ynyl)-pyridine-2-carboxylic acid methyl ester. Toa dry flask were added intermediate 11b prepared in general method P(2.98 g, 11.33 mmol, 1 equiv), triphenylphosphine (238 mg, 0.91 mmol,0.08 equiv), copper (I) iodide (172.6 mg, 0.91 mmol, 0.08 equiv),palladium acetate (101.6 mg, 0.45 mmol, 0.04 equiv) and triethylamine(42 mL). The mixture was deaerated with nitrogen, followed by additionof 3,3-Diethoxy-propyne (Aldrich) (2.90 g, 22.7 mmol, 2 equiv). Themixture was stirred at rt for 3 h. The solvent was removed under vacuumto give a dark residue. The residue was purified by chromatography togive a yellow oil 11c (R9′=3,3-Diethoxy-prop-1-ynyl) (3 g, 100%): ¹H NMR(300 MHz, CDCl₃) δ 8.69 (dd, J=0.8, 5.0, 1), 8.15 (d, J=0.8, 1.4, 1),7.49 (dd, J=1.7, 5.0, 1), 5.48 (s, 1), 3.99 (s, 3), 3.82-3.73 (m, 2),3.71-3.62 (m, 2), 1.26 (t, J=7.2, 6). MS (ESPOS): 264.5 [M+H]⁺.

4-(3,3-Diethoxy-1-propyl)-piperidine-1,2-dicarboxylic acid 2-methylester 11d (R9′=3,3-diethoxy-1-propyl). To a mixture of 11c(R9′=3,3-Diethoxy-prop-1-ynyl) (3 g) in MeOH (15 mL), acetic acid (15mL) and water (15 mL) was added platinum oxide (1.0 g). The mixture waspurged and charged with hydrogen (50 psi) and shaken at rt for 5 hr. Theplatinum oxide was removed by filtration and the filtrate wasconcentrated to give the desired product 11d (R9′=3,3-diethoxy-1-propyl)(2.45 g, 79%) as an oil: MS (ESPOS): 296.5 [M+Na]⁺.

4-(3,3-Diethoxy-1-propyl)-piperidine-1,2-dicarboxylic acid 1-allyl ester2-methyl ester 11e (R9′=3,3-Diethoxy-1-propyl, P=Alloc). To a solutionof 11d (R9′=3,3-diethoxy-1-propyl) (2.4 g, 8.79 mmol, 1 equiv) andpyridine (1.26 mL, 11.9 mmol, 1.35 equiv) in THF (29 mL) at 0° C. wasadded dropwise a solution of allyl chloroformate (0.96 mL, 11.9 mmol,1.4 equiv). The mixture was slowly warmed to rt and stirred at rt for 3hr. The solution was filtered and solvent was removed under vacuum. Theresidue was purified by chromatography to furnish 11e(R9′=3,3-diethoxy-1-propyl, P=Alloc) (2.1 g, 66%) as a clear oil: MS(ESPOS): 380.6 [M+Na]⁺.

4-(3-Oxo-propyl)-piperidine-1,2-dicarboxylic acid 1-allyl ester 2-methylester. A solution of 11e (R9′=3,3-diethoxy-1-propyl, P=Alloc) (2.03 g)in acetic acid (32 mL) and water (8 mL) was stirred at rt overnight. Thesolvent was removed under high vacuum. The residue was diluted withethyl acetate, and washed with sat. sodium bicarbonate (1×) and brine(1×). The organic layer was dried and concentrated. The residue waspurified by chromatography to give methyl ester 11e (R9′=3-oxo-propyl,P=Alloc) (1.2 g, 75%) as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 9.75 (t,J=1.5, 1), 5.96-5.82 (m, 1), 5.30-5.16 (m, 2), 4.57 (d, J=5.4, 2), 4.46(t, J=6.0, 1), 3.74-3.65 (m, 1), 3.71 (s, 3), 3.42-3.32 (m, 1),2.48-2.41 (m, 2), 2.02-1.35 (m, 7); MS (ESPOS): 306.5 [M+Na]⁺.

4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-1,2-dicarboxylic acid 1-allylester 2-methyl ester. To a mixture of 11e (R9′=3-oxopropyl, P=Alloc)(248 mg, 0.87 mmol, 1 equiv) and 1,2-ethanedithiol (0.147 mL, 1.75 mmol,2 equiv) under nitrogen was added borontrifluoride-acetic acid complex(0.122 mL, 0.87 mmol, 1 equiv). The mixture was stirred vigorously for 1hr. The mixture was diluted with hexane and washed with sat. sodiumbicarbonate (3×) and brine (1×). The organic layer was dried andconcentrated. The residue was purified by chromatography to furnish 11e(R9′=2-[1,3]dithiolan-2-yl-ethyl, P=Alloc) (144 mg, 46%) as an oil: MS(ESPOS): 382.5 [M+Na]⁺.

4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-1,2-dicarboxylic acid 1-allylester 11f (R9′=(2-[1,3]dithiolan-2-yl-ethyl), P=Alloc). To a mixture of11e (R9′=2-[1,3]dithiolan-2-yl-ethyl, P=Alloc) (144 mg, 0.40 mmol, 1equiv) in THF (3 mL) and water (1 mL) was added lithium hydroxidemonohydrate (67 mg, 1.6 mmol, 4 equiv). The mixture was stirred at rtovernight. THF was removed under vacuum. The aqueous layer was taken upin ethyl acetate, partitioned with 10% citric acid. The organic layerwas washed with water (1×), brine (1×), dried and concentrated to give11f (R9′=(2-[1,3]dithiolan-2-yl-ethyl), P=Alloc) (127 mg, 92%) as asyrup: ¹H NMR (300 MHz, CDCl₃) δ5.96-5.83 (m, 1), 5.30-5.17 (m, 2), 4.59(d, J=5.4, 2), 4.48 (t, J=6.4, 1), 4.41 (t, J=6.9, 1), 3.75-3.64 (m, 1),3.44-3.33 (m, 1), 3.25-3.12 (m, 4), 2.05-1.35 (m, 9). MS (ESPOS): 346.5[M+H]⁺.

4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.To a mixture of 2b (R2′=H) (95 mg, 0.33 mmol, 1 equiv) in dry DMF (0.8mL) at 0° C. was added triethylamine (0.23 mL, 1.65 mmol, 5 equiv),followed by the addition of Bis(trimethylsilyl)trifluoroacetamide (0.13mL, 0.49 mmol, 1.5 equiv). The reaction mixture was stirred at 0° C. for10 minutes, and then was stirred at rt for 50 minutes. To the reactionmixture were added acid 11f (R9′=2-[1,3]dithiolan-2-yl-ethyl, P=Alloc)(115 mg, 0.33 mmol, 1.0 equiv) and HATU (158 mg, 0.42 mmol, 1.3 equiv).The reaction mixture was stirred at rt for 3 h. The reaction mixture wasevaporated to dryness, taken up in ethyl acetate, washed with 10% citricacid (1×), water (1×), sat. NaHCO₃ (1×) and brine. The organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified bychromatography to give the Alloc protected lincosamide analog (133 mg,70%) as a syrup: MS (ESPOS): 579.8 [M+H]⁺.

To a solution of the above Alloc protected lincosamide (103 mg, 0.18mmol, 1 equiv) in THF (2.3 mL) were added dimedon e (0.25 g, 1.78 mmol,10 equiv) and tetrakis-(triphenylphosphine) palladium (41.1 mg, 0.036mmol, 0.2 equiv). The mixture was stirred at rt overnight. The solventwas removed under vacuum and the residue was purified by chromatographyto furnish the title compound of example 27 (34 mg, 49%) as a slightlyyellow solid: ¹H NMR (300 MHz, CD₃OD) δ 5.23 (d, J=5.7, 1), 4.45 (t,J=6.9, 1), 4.18-4.01 (m, 3), 3.81-3.77 (m, 1), 3.56-3.47 (m, 2),3.25-3.07 (m, 5), 2.66-2.56 (m, 1), 2.18-2.13 (m, 1), 2.10 (s, 3),1.94-1.63 (m, 4), 1.55-1.35 (m, 3), 1.12-0.98 (m, 2), 0.95-0.88 (m, 6);MS (ESPOS): 495.6 [M+H]⁺.

Example 27

There is no Example 27.

Example 28 4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-1,2-dicarboxylic acid1-allyl ester 11f (R9′=4-Methyl-thiazol-2-yl, P=Alloc). Thisintermediate was prepared using the reaction sequence described ingeneral method P, Scheme 11, from intermediate 11b, using4-tert-Butoxycarbonylethyne (Aldrich) as the alkyne. The 4-methylthiazole moity was installed by elaboration of protected dicarboxylicacid 11e (R9′=(propionic acid tert-butyl ester, P=Alloc) by methods wellknown to persons skilled in the art. Ester deprotection as performed ingeneral method P provided the desired carboxylate intermediate 11f(R9′=4-Methyl-thiazol-2-yl, P=Alloc).

4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.Coupling of 2b (R2′=H) to protected amino acid 11f(R9′=4-Methyl-thiazol-2-yl, P=Alloc) and deprotection were performed bythe procedure described in example 26 to furnish the title lincosamideof example 28: (300 MHz, CD₃OD) δ 6.80 (s, 1) 5.07 (d, J=5.5, 1), 4.43(dd, J=3.3, 9.9 1), 3.91-3.86 (m, 2), 3.60 (m, 1), 3.50-3.45 (m, 1),3.30 (d, J=3.3, 10.4, 1), 2.89-2.82 (m, 2), 2.76-2.67 (m, 1), 2.19 (s,3), 1.96 (s, 3), 1.77-1.73 (m, 1), 1.61-1.57 (m, 3), 1.22-1.09 (m, 2),0.72 (d, J=6.9, 6); MS (ESPOS): 488.4 [M+H]⁺.

Example 29 4-(3-Methoxyiminoprop-1-yl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

11e (R9′=3-methoxyimino-propyl, P=Alloc). To a solution of 11e(R9′=3-oxopropyl, P=Alloc) prepared in example 26 (129 mg, 0.45 mmol) inethanol (1.3 mL) were added methoxylamine hydrochloride and pyridine.The reaction mixture was refluxed for 2 hr. The solvent was removedunder vacuum. The residue was taken up into ethyl acetate, washed with10% citric acid and brine, dried and concentrated to provide 11e(R9′=3-methoxyimino-propyl, P=Alloc) (129 mg, 91%) as a clear oil: MS(ESPOS): 334.5 [M+Na]⁺.

4-(3-Methoxyimino-propyl)-piperidine-1,2-dicarboxylic acid 1-allyl ester11f (R9′=(3-methoxyimino-propyl), P=Alloc). To a mixture of ester 11e(R9′=(3-methoxyimino-propyl), P=Alloc) (129 mg, 0.41 mmol, 1 equiv) inTHF (1.5 mL) and water (0.5 mL) was added lithium hydroxide monohydrate(69 mg, 1.6 mmol, 4 equiv). The mixture was stirred at rt overnight. THFwas removed under vacuum. The aqueous layer was taken up in ethylacetate, partitioned with 10% citric acid. The organic layer was washedwith water (1×), brine (1×), dried and concentrated to give 11f(R9′=3-methoxyimino-propyl, P=Alloc) (114 mg, 93%) as a clear oil: ¹HNMR (300 MHz, CDCl₃) δ 7.31 (t, J=6.2, 0.6H), 6.60 (t, J=5.4, 0.4H),5.96-5.82 (m, 1), 5.30-5.16 (m, 2), 4.58 (d, J=5.7, 2), 4.83 (t, J=6.5,1), 3.83 (d, J=0.3, 1.2H), 3.78 (d, J=0.6, 1.8H), 3.77-3.62 (m, 1),3.42-3.30 (m, 1), 2.38-2.26 (m, 1), 2.23-2.14 (m, 1), 2.08-1.85 (m, 2),1.82-1.62 (m, 2), 1.53-1.35 (m, 3); MS (ESPOS): 321.2 [M+Na]⁺.

4-(3-Methoxyimino-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.To a mixture of 2b (R2′=H)(109.8 mg, 0.38 mmol, 1 equiv) in dry DMF (0.9mL) at 0° C. was added triethylamine (0.26 mL, 1.91 mmol, 5 equiv),followed by the addition of bis(trimethylsilyl)trifluoroacetamide (0.15mL, 0.57 mmol, 1.5 equiv). The reaction mixture was stirred at 0° C. for10 minutes, and then was stirred at rt for 50 minutes. To the reactionmixture were added the protected amino acid 11f(R9′=3-methoxyimino-propyl, P=Alloc) (113.6 mg, 0.38 mmol, 1.0 equiv)and HATU (182 mg, 0.48 mmol, 1.26 equiv). The reaction mixture wasstirred at rt for 3 h. The reaction mixture was evaporated to dryness,taken up in ethyl acetate, washed with 10% citric acid (1×), water (1×),sat. NaHCO₃ (1×) and brine. The organic layer was dried over Na₂SO₄ andconcentrated. The residue was purified by chromatography to furnish theAlloc protected lincosamide product(107 mg, 53%): MS (ESPOS): 532.4[M+H]⁺.

To a mixture of the above Alloc protected lincosamide (107 mg, 0.20mmol, 1 equiv) in THF (2.6 mL) were added dimedone (282 mg, 2.01 mmol,10 equiv) and tetrakis(triphenylphosphine)palladium (46.5 mg, 0.04 mmol,0.2 equiv). The mixture was stirred at rt overnight. The solvent wasremoved under vacuum and the residue was purified by chromatography togive the title compound of example 29 (28 mg, 31%) as a white solid: ¹HNMR (300 MHz, CD₃OD) δ 7.36 (t, J=6.2, 0.68H), 6.66 (t, J=5.4, 0.32H),5.23 (d, J=5.7, 1), 4.16 (dd, J=3.2, 10.1, 1), 4.10-4.01 (m, 2), 3.81(s, 1), 3.79 (d, J=3.3, 1), 3.74 (s, 2), 3.50 (dd, J=3.3, 9.9, 1),3.30-3.22 (m, 1), 3.18-3.10 (m, 1), 2.67-2.55 (m, 1), 2.40-2.31 (m, 1),2.25--2.12 (m, 2), 2.10 (s, 3), 1.97-1.88 (m, 1), 1.76-1.65 (m, 1),1.59-1.38 (m, 3), 1.14-1.01 (m, 2), 0.90 (d, J=6.9, 6); MS (ESPOS):448.4 [M+H]⁺.

Example 30 4-(3-Ethoxyimino-prop-1-yl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Synthesis of the title compound in example 30 was performed as describedin example 29 from intermediate 11e (R9′=3-oxopropyl, P=Alloc)substituting ethoxylamine hydrochloride in the imine forming step: MS(ESPOS): 462.4 [M+H]⁺.

Example 31 4-[2-(5-Ethyl-isoxazol-3-yl)-ethyl]-piperidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Synthesis of the title compound in example 31 was performed as inexample 29 from intermediate 11e (R9′=3-oxopropyl, P=Alloc) substitutinghydroxylamine hydrochloride in the imine forming step to furnish 11e(R9′=3-hydroxyimino-propyl, P=Alloc). The isoxazole heterocycle wasinstalled by elaboration of intermediate 11e (R9′=3-hydroxyimino-propyl,P=Alloc) by cycloaddition of 1-butyne in the presence ofN-chlorosuccinimide and TEA. Coupling and deprotection were performed asdescribed in example 29: MS (ESPOS): 486.3 [M+H]⁺.

Example 32 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide4-Position Stereoisomer I and 4-position Stereoisomer II

4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide(position 4 stereoisomer I high Rf and position 4 stereoisomer II lowRf). To a solution of Boc protected amino acid 12d (P=Boc, R9=propyl,m=1) prepared in general method Q, synthetic sequence depicted in scheme12 (310 mg, 1.15 mmol) in DMF (3 mL) at 0° C., 7-Cl MTL 6b (R²=H, R³=Cl)(306 mg, 1.15 mmol) HBTU (469 mg, 1.3 mmol) and DIEA (290 μL, 2.3 mmol)was added, left stirred at room temperature overnight. DMF was removedby rotary evaporation under high vacuum. The residue obtained waspurified on silica gel column chromatography (3% MeOH in DCM) to obtainthe desired Boc protected 4-F lincosamide (451 mg, 75%) a light brownoil: ¹H NMR (300 MHz, CD₃OD) δ 5.29 (d, J=5.7, 1), 4.50 (m, 3), 4.10 (m,1), 3.60 (m, 3), 2.51 (m, 1), 2.11(m, 4), 1.70 (m, 2), 1.50 (m, 9), 0.96(t, J=7.2, 3); MS (ESPOS): 529 [M+H]+.

To a solution of the above Boc protected 4-fluoro lincosamide (451 mg,0.85 mmol) in DCE (6 mL), triethylsilane (0.16 mL), TFA (2 mL) and water(0.16 mL) was added and stirred at room temperature for 1.5 hr. Thereaction solvent was removed in vacuo. The resulting residue waspurified by silica gel column chromatography using 10% MeOH in DCM aseluent to obtain the title compound for example 32 4 stereoisomer I(high TLC Rf) (165 mg, 45%): ¹H NMR (300 MHz, CD₃OD) δ 5.29 (d, J=5.7,1), 4.59 (m, 2), 4.32 (d, J=9.9, 1), 4.07 (dd, J=5.7, 10.2, 1), 3.81 (d,J=3.3, 1), 3.59 (m, 3), 3.01 (d, J=3.0, 1), 2.83 (m, 1), 2.14 (m, 4),1.86 (m, 2), 1.50 (m, 5), 0.99 (t, J=7.2, 3); MS (ESPOS) 429 [M+H]+; and4 stereoisomer II (low TLC Rf) (165 mg, 45%); ¹H NMR (300 MHz, CD₃OD) δ5.29 (d, J=5.7, 1), 4.59 (m, 3), 4.29 (d, J=10.2, 1), 4.08 (dd, J=5.7,10.2, 1), 3.85 (d, J=3.3, 1), 3.59 (m, 4), 2.60 (m, 1), 2.11 (m, 3),1.88 (m, 2), 1.50 (m, 5), 0.99 (t, J=7.2, 3); MS (ESPOS); 429 [M+H]+.

Example 33 4-Fluoro4-propyl-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-Fluoro4-propyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester,12d (P=Boc, R⁹=n-propyl, m=2). The synthesis of Boc protected 4-fluoroamino acid 12d from the starting material(2S)-4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester usesgeneral method Q, depicted in scheme 12. The preparation of the startingmaterial (2S)-4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl esteris described by Bousquet, Y.; Anderson, P. C.; Bogri, T.; Duceppe J.;Grenier, L.; Guse, I.; Tetrahedron, 1997, 53 15671-15680.

A rapidly stirred solution of 4-oxo-piperidine-1,2-dicarboxylic acid1-tert-butyl ester 12a (m=2, P=H, P₂=Boc) (16.0 g, 0.066 mol) (preparedby the method described by Bousquet et al. Tetrahedron, 1997, 53, 15671)in DMF (200 mL) was treated with solid cesium carbonate (10.7 g, 0.033mol) and methyl iodide (4.5 mL, 0.072 mol). The reaction mixture wasstirred 5 h, diluted with EtOAc and extracted with saturated aq. sodiumbicarbonate, 10% aq. citric acid and brine, the organic layer wasseparated and dried over sodium sulfate, friltered and evaporated todriness. The product obtained on removal of solvent was azeotropicallydried by evaporation from dry benzene to afford 14.8 g (98%) of thedesired product 4-Oxo-piperidine-1,2-dicarboxylic acid 1-tert-butylester 2-methyl ester 12a (m=2, P=Me, P₂=Boc) as an oil: TLC R_(f) 0.53(Hexanes/EtOAc, 1:1); ¹H NMR (300 MHz, CDCl₃) δ 5.33 (broad m, 0.5)rotamer, 5.06 (broad m, 0.5) rotamer, 4.31-4.19 (m, 1), 3.95 (s, 3),3.95-3.70 (m, 1), 3.16-2.97 (m, 2), 2.71 (m, 2), 1.68 (broad s, 9).

A 0° C. stirred solution of 4-oxo-piperidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester 12a (m=2, P=Me, P₂=Boc) (5.17 g, 0.02mol) in DCM (60 mL) was treated with tetraallyltin (Aldrich) (5.3 mL,0.022 mol) followed by dropwise addition of BF₃.OEt₂ (2.5 mL, 0.02 mol).The reaction mixture was stirred 1 h, then aq. 1M potassium fluoride(38.0 mL) and celite (5 g) was added and the reaction mixture wasstirred 3 h. The reaction mixture was filtered and concentrated todryness, the residue was dissolved in DCM and washed with water andbrine, dried over MgSO₄ and evaporated to dryness. The residue obtainedwas purified by silica gel column chromatography (DCM 100% to DCM:acetone 9:1) to afford 3.85 g (64%) of the desired product4-allyl-4-hydroxy-piperidine-1,2-dicarboxylicacid 1-tert-butyl ester2-methyl ester 12b (m=2, P=Me, P₂=Boc, R^(9′)=allyl) as an oil.

¹H NMR (300 MHz, CDCl₃) δ 6.11-5.97 (m, 1), 5.42-5.32 (m, 2), 5.06(broad d, J=6.0, 0.5) rotamer, 4.87 (broad d, J=6.0, 0.5) rotamer,4.18-4.03 (m, 1), 3.93 (s, 3), 2.48-2.37 (m, 2), 1.98-1.43 (m, 11); MS(ESPOS): 322.0 [M+Na]⁺.

A stirred suspension of 12b (m=2, P=Me, P₂=Boc, R^(9′)=allyl) (3.80 mL,1.27 mmol) and 10% Pd/C (degusa wet form 50% w/w) (1.35 g, 1.3 mmol) inMeOH (80 mL) was stirred 6 h under 1 atm hydrogen. The reaction mixturewas filtered through celite and evaporated to dryness and driedazeotropically by evaporation from toluene the residue obtained (3.15 g)was used in the next step without further purification.

To a stirred −-78° C. solution of DAST (1.7 mL, 1.3 mmol) in DCM (50 mL)was added 4-Hydroxy-4-propyl-piperidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester in DCM (30 mL). The reaction mixturewas then stirred at for 1 h, then allowed to warm to −40° C. for 5 h.Additional DAST (0.4 mL) was added and the reaction mixture stirred anadditional 2 h, saturated aq. K₂CO₃ (20 mL), and water (60 mL) was addedfollowed by diethyl ether (500 mL) the organic layer was separated,washed with brine dried over sodium sulfate and evaporated to dryness.The resulting crude fluorinated product was purified by silica gelcolumn chromatography (hexanes-EtOAc 9:1). The residue obtained bychromatographic purification was dissolved in dioxane (65 mL) and water(26 mL) cooled to 0° C. and treated with OSO₄ (0.65 mL, 4% aq. solution)and 30% H₂O₂ (10 mL). The reaction mixture was stirred overnightconcentrated to dryness, the residue was dissolved in DCM and theorganic layer washed with water (100 mL) 25% aq. Na₂SO₃ (2×100 mL) andbrine (100 mL), dried over Na₂SO₄ and evaporated to dryness. The residueobtained was purified by silica gel column chromatography (hexanes-EtOAc9:1) to afford (1.08 g, 34%) of the desired product4-fluoro-4-propyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester2-methyl ester 12c (m=2, P=Me, P₂=Boc, R⁹=n-propyl) as an oil.

¹H NMR (300 MHz, CDCl₃) δ 4.59 (dd, J=6.0, 6.0, 1), 3.82-3.69 (m, 1),3.74 (s, 3), 3.28 (m, 1), 3.29-2.04 (m, 2), 1.91-1.71 (m, 3), 1.60-1.31(m, 6), 1.45 (s, 9), 0.92 (t, J=7.1, 3); MS (ESPOS): 204.1 (M+H-Boc),326.3 [M+Na]⁺.

The synthesis of the title compound in example 33 From 12d (P=Boc,R⁹=n-propyl, m=2) is readily accomplished using the coupling anddeprotection conditions from example 32.

MS (ESPOS): 443.1 [M+M]⁺; HPLC: C,₈ 3.5 μm, 4.6×30 mm Column; gradienteluent 2%-98% MeCN over 10 min; 1.5 mL/min): R_(t)=3.738 min.

Example 34 4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.A stirred suspension of 12d (P=Boc, R⁹=C₃H₇, m=1) (164 mg, 0.57 mmol)prepared by general method Q, depicted in scheme 12, was suspended indry acetonitrile (4 mL). Triethylamine (332 μL, 3.02 mmol) was added andthe reaction mixture was cooled to 0° C. Isobutyl chloroformate (78 μL,0.57 mmol) was added and after 10 min the reaction was allowed to warmto 4° C. After 1.5 h, a solution of MTL 1a (151 mg, 0.57 mmol) in 1:1acetone: water (4 mL) was added and the reaction mixture was stirred for10 h at rt. The reaction mixture was evaporated to dryness andchromatographed on silica (95:5 dichloromethane/MeOH to 95:8dichloromethane/MeOH) to provide the product as a colorless oil (137 mg,45%): TLC R_(f)=0.32 (9:1 dichloromethane/MeOH); MS (ESPOS): 411[M+H-Boc]+, 511 [M+H]+.

To a solution of the above Boc protected lincosamide (125 mg) in DCM(2.0 mL) was added a solution of DCE (10.0 mL), trifluoroacetic acid (5mL) methyl sulfide (0.3 mL), and water (0.3 mL). The reaction mixturewas stirred at rt for 40 min then diluted with DCE (25.0 mL). Thesolvent was removed under vacuum and co-evaporated with DCE twice. Theresidue was purified by chromatography on fluorosil (20% MeOH 0.25 MNH₃/DCM) to provide the title compounds as a colorless solid (30.0 mg,30%): MS (ESPOS): 411.6 [M+H]+.

Example 35 4-Fluoro-4-butyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide4-Position Stereoisomer I and 4-Position Stereoisomer II

4-Hydroxy-4-butylproline methylester 12b (P=Boc, m=1, R⁹=n-butyl). To astirred solution n-butyllithium (165 mg, 2.6 mmol) in THF (5 mL) at −78°C. was added 12a (P=Boc, P₂=Me, m=1) (570 mg, 2.3 mmol) in THF (5 mL).The reaction mixture was stirred at −78° C. for 2 hr and then at −40° C.for an additional 1 hr. EtOAc (20 mL) was added, followed by NH₄Cl (5mL, 10%) and water (10 mL). Organic layer was separated, dried oversodium sulflate and evaporated to dryness. The residue obtained waspurified by silica gel column chromatography using 50% EtOAc in hexanesas eluent to provide 4-hydroxy-4-butylproline methylester 12b (P=Boc,m=1, R9=n-butyl) as a colorless oil (0.52 g, 73%): ¹H NMR (300 MHz,CDCl₃) δ 4.33 (m, 1), 3.76 (d, J=4.8, 3), 3.62 (m, 2), 3.28 (m, 1), 2.13(m, 1), 2.02 (m, 1), 1.57 (m, 2), 1.29 (m, 12), 0.88 (m, 3); MS (ESPOS):324 [M+Na]+.

4-Fluoro-4-butylproline methyl ester 12c (P=Boc, m=1, R⁹=n-butyl). To astirred solution of DAST (0.55 g, 3.4 mmol) in DCM (5 mL) at −78° C.,4-hydroxyproline 12b (P=Boc, m=1, R9=n-butyl) (520 mg, 1.7 mmol) in dryDCM (5 mL) was added slowly. The mixture was stirred at −78° C. for 1 hand then at −10° C. for an additional 1 h. DCM (50 mL) was added,followed by aq. NH₄Cl (10%, 30 mL). The organic layer was separated,dried over sodium sulfate and evaporated to dryness. The residueobtained was purified by column chromatography using 5% EtOAc in hexanesto obtain 4-fluoro-4-butylproline methyl ester 12c (P=Boc, m=1,R9=n-butyl) (270 mg, 52%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ4.41 (m, 2), 3.83 (m, 1), 3.71 (s, 3), 3.45 (dd, J=12.3, 32.7, 2), 2.48(m, 1), 1.73 (m, 2), 1.40 (m, 12), 0.89 (m, 3); MS (ESPOS): 326 [M+Na]⁺.

4-Fluoro-4-butylproline 12d (P=Boc, m=1, R9=n-butyl). To a solution of12c (0.27 g, 0.89 mmol) in THF (10 mL) and water (3 mL) was addedlithium hydroxide monohydrate (45 mg, 1.06 mmol). The reaction mixturewas stirred at room temperature overnight. THF was removed and theresidue was purified by column chromatography using 10% MeOH in DCM aseluent to obtain 4-Fluoro-4-butylproline 12d (P=Boc, m=1, R9=n-butyl)(0.26 g, 100%) as a colorless oil: ¹H NMR (300 MHz, CD₃OD) δ 4.30 (m,1), 3.72 (m, 1), 3.49 (m, 1), 3.39 (m, 1), 2.58 (m, 1), 2.02 (m, 2),1.72 (m, 13), 0.93 (t, J=6.6, 3); MS (ESNEG): 288 [M−1]⁻.

4-Fluoro-4-butyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide:4 stereoisomer I and 4 stereoisomer II. To a solution of 12d (P=Boc,m=1, R9=n-butyl) (125 mg, 0.43 mmol) in DMF (3 mL) at 0° C., 7-Cl MTL,6b (R2=H, R3=Cl)(117 mg, 0.43 mmol), HBTU (180 mg, 0.47 mmol) and DIEA(111 mg, 0.86 mmol) was added and left stirred at room temperature forovernight. Solvent was removed and the residue was purified on silicagel column chromatography using 2% MeOH in DCM to obtain the desired Bocprotected lincosamide intermediate (170 mg, 72%) as a light brownliquid: ¹H NMR (300 MHz, CD₃OD) δ 5.29 (d, J=5.4, 1), 4.57 (m, 3), 4.39(m, 1), 4.03 (m, 2), 3.74 (m, 3), 3.25 (m, 1), 2.51 (m, 1), 2.12(m, 3),1.85 (m, 3), 1.46 (s, 9), 1.36 (m, 6), 0.93 (t, J=6.6, 3); MS (ESPOS):543 [M+H]⁺.

To a solution of the above Boc protected lincosamide (170 mg, 0.31 mmol)in DCE (6 mL) was added triethylsilane (0.16 mL), TFA (2 mL) and water(0.16 mL). The reaction mixture was stirred at room temperature for 1hr. Solvent was removed and the residue was purified on silica gelcolumn chromatography using 10% MeOH in DCM to obtain4-fluoro-4-butyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide,4 stereoisomer I (14 mg, 10%); ¹H NMR (300 MHz, CD₃OD) δ 5.30 (d, J=6.0,1), 4.54 (m, 3), 4.29 (d, J=10.2, 1), 4.09 (dd, J=5.6, 10.2, 1), 3.80(d, J=3.0, 1), 3.56 (m, 3), 2.70 (m, 1), 2.14 (m, 4), 1.87 (m, 2), 1.43(m, 7), 0.94 (t, J=7.2, 3); MS (ESPOS): 443 [M+H]. 4-Fluoro-4-butyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide,4 stereoisomer II (3 mg, 2%); ¹H NMR (300 MHz, CD₃OD) δ 5.30 (d, J=6.0,1), 4.54 (m, 3), 4.29 (d, J=10.2, 1), 4.09 (dd, J=5.6, 10.2, 1), 3.80(d, J=3.0, 1), 3.56 (m, 3), 2.70 (m, 1), 2.14 (m, 4), 1.87 (m, 2), 1.43(m, 7), 0.94 (t, J=7.2, 3); (ESPOS): 443 [M+H]⁺.

Example 36 4-Fluoro-4-ethyl-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-Fluoro-4-ethyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester,12d (P=Boc, m=2, R⁹=n-ethy). The synthesis of boc-protected 4-fluoroamino acid 12d from the starting material(2S)-4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester usesgeneral method Q, depicted in scheme 12, utilizingtrimethylsilylacetylene anion as a two carbon synthon in the 4-ketonealkylation step. Preparation of the starting material,4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester is describedby Bousquet, Y.; Anderson, P. C.; Bogri, T.; Duceppe J.; Grenier, L.;Guse, I.; Tetrahedron, 1997, 53 15671-15680. The synthesis of the titlecompound in example 36 from 12d (P=Boc, m=2, R⁹=ethyl) is readilyaccomplished using the coupling and deprotection conditions from example34. MS (ESPOS): 429.1 [M+H]⁺.

Example 37 4-Propylidene-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-Oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methylester. To (2S)-4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester(0.52 g, 2.15 mmol) in methanol (10 mL), 2 M solution ofTMS-diazomethane (2 mL, 4 mmol) in hexane was added and stirred at roomtemperature for 15 min. The reaction solvent was removed and the methylester product obtained (4-oxo-piperidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester) was used as such for the nextreaction (0.55 g, 100%): MS (ESPOS): 258 [M+H]⁺; ¹H NMR (300 MHz, CD₃OD)δ 5.13, 4.86 (bs, 1), 4.02-4.11 (m, 1), 3.73 (s, 3), 3.67-3.72 (m, 1),2.78 (d, J=4.2 Hz, 2), 2.51 (bs, 2), 1.46 (bs, 9).

4-Propylidene-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester2-methyl ester. Propyltriphenylphosphonium bromide (1.24 g, 3.22 mmol)in THF (10 mL) was added to hexane washed sodium hydride (123 mg, 3.22mmol), in THF (10 mL) and stirred at room temperature for 3 h. Methylester 12a (P=Boc, m=2, P2=Me) (0.55 g, 2.15 mmol) in THF (5 mL) wasadded to the above reaction mixture slowly and then allowed to stir foradditional 2 h. It was then poured into water and extracted with ethylacetate (30 mL). The organic phase was dried with magnesium sulfate,filtered and evaporated to dryness, the resulting residue waschromatographed using 20% EtOAc in hexanes to provide the product4-propylidene-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester2-methyl ester. (0.100 g, 16%): MS (ESPOS): 284 [M+H]+; ¹H NMR (300 MHz,CD₃OD) δ 5.18 (m, m), 4.60-4.93 (m, 1), 3.91 (m, 1), 3.67 (s, 3),2.94-3.04 (m, 2), 2.40-2.48 (m, 2), 1.99-2.06 (m, 1), 1.85-1.97 (m, 2),1.38 (bs, 9), 0.85 (t, J=5 Hz, 3).

4-Propylidene-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester. Tothe 4-propylidene-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester2-methyl ester. (0.100 g, 0.353 mmol) in THF (10 mL) was added lithiumhydroxide (0.50 g, 11.6 mmol) in water (2 mL) and the reaction mixturestirred at room temperature for 16 h. It was then poured into water andextracted with ether (20 mL). The water layer was then acidified with10% HCl (5 mL) and extracted with ethyl acetate (30 mL). The productcarboxylic acid 4-propylidene-piperidine-1,2-dicarboxylic acid1-tert-butyl ester obtained after drying and removal of solvent wastaken as such for the next step. MS (ESNEG): 268 [M−1]−; ¹H NMR (300MHz, CD₃OD) δ 5.18 (m, m), 4.60-4.93 (m, 1), 3.91 (m, 1), 2.94-3.04 (m,2), 2.40-2.48 (m, 2), 1.99-2.06 (m, 1), 1.85-1.97 (m, 2), 1.38 (bs, 9),0.85 (t, J=5 Hz, 3).

4-Propylidene-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.To a stirred solution of 2b (R2′=H) (32 mg, 0.12 mmol), DIEA (0.2 mL,1.20 mmol), 4-propylidene-piperidine-1,2-dicarboxylic acid 1-tert-butylester (37 mg, 0.14 mmol) in DMF (5 mL) was added HBTU (57 mg, 0.16 mmol)and the mixture was stirred at room temperature for 2 h. Most of the DMFwas removed under high vacuum, and the crude material was taken up inethyl acetate (50 mL) and washed with saturated sodium bicarbonate (10mL). Solvent was removed under vacuum, and the product was purified bysilica gel column chromatography using ethyl acetate as eluent to obtainthe desired Boc protected lincosamide (50 mg, 83%): MS (ESPOS): 503(M−1); ¹H NMR (300 MHz, CD₃OD) δ 5.19-5.27 (m, 2), 4.10-4.26 (m, 2),3.90-4.05 (m, 2), 3.83-3.90 (m, 2), 3.49-3.88 (m, 2), 3.06 (m, 2), 2.57(m, 2), 1.90 (s, 3), 1.47 (bs, 9), 0.88-0.95 (m, 9).

To the above Boc protected lincosamide (50 mg, 0.10 mmol) indichloroethane (6 mL), triethylsilane (0.15 mL) was added, followed by93% aq. trifluoroacetic acid (2.15 mL). After stirring at rt for 1 hr,the solvent was removed at 45° C. under reduced pressure. The crudeproduct obtained was purified by silica gel column chromatography using10% MeOH in DCM as eluent to the title compound (5 mg, 12%): ¹H NMR (300MHz, CD₃OD) δ 5.40 (m, 1), 5.24 (d, J=3.8 Hz, 1), 4.16-4.20 (m, 1),4.04-4.09 (m, 2), 3.81 (t, J=2.2 Hz, 1), 3.49-3.55 (m, 2), 2.50-2.92 (m,3), 2.00-2.25 (m, 6), 2.10 (s, 3), 0.89-0.98 (m, 9). MS (ESPOS): 403[M+H]+.

Example 38 4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Coupling of Boc-Protected Amino Acid to 2b (R^(2′)=H).

To a solution of Boc amino acid 21k (R⁹=n-propyl, R^(9b)=H, m=1)prepared by general method S depicted in scheme 21 (69 mg, 0.26 mmol, 1equiv), 2b (R^(2′)=H) (74 mg, 0.26 mmol, 1 equiv) and HBTU (107 mg,0.28, 1.1 equiv) in DMF (2.5 mL) at 23° C. was addedN,N-diisopropylethylamine (89 μL, 0.51 mmol, 2 equiv). The reaction wasstirred at 23° C. for 2.5 h then concentrated in vacuo to remove DMF.The resulting residue was dissolved in EtOAc (70 mL), then washed with1:1 brine: 10% aqueous citric acid (50 mL), saturated aqueous NaHCO₃ (50mL), brine (30 mL), dried (MgSO₄), filtered and concentrated to give 107mg of the desired coupled product. This material was used withoutfurther purification in the final deprotection step: ¹H NMR (300 MHz,CD₃OD) δ 5.39 (br d, J=14.4 Hz, 1H), 5.19 (d, J=5.7 Hz, 1H), 4.10-3.82(m, 4H), 3.55-3.48 (m, 1H), 2.45 (br s, 2H), 2.05 (s, 3H), 2.04-1.94 (m,2H), 1.47 (s, 9H), 1.46-1.37 (m, 2H), 0.96-0.83 (m, 9H); MS (ESPOS):503.3 [M+H]+.

Boc-Deprotection to Give4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.

To a solution of the above Boc-carbamate lincosamide (35 mg, 0.070 mmol,1 equiv) in DCE (5.0 mL) at 23° C. was added H₂O (0.20 mL) followed byTFA (2.0 mL). The reaction was stirred at 23° C. for 30 min then treatedwith toluene (40 mL) then concentrated to a volume of 10 mL, thentreated with a second portion of toluene (40 mL) and concentrated todryness. The crude product was purified via semi-prep HPLC (WatersNova-Pak® HR C₁₈, 6 μm particle size, 60 Å pore size, 25 mm diameter×100mm length, 5-60% acetonitrile in H₂O/0.1% AcOH over 30 min, 20 mL/minflow rate) to give 16 mg of pure4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide:¹H NMR (300 MHz, D₂O) δ 5.51 (br s, 1H), 5.33 (br d, J=5.4 Hz, 1H), 4.18(s, 2 H), 4.13-3.98 (m, 2H), 3.86 (br s, 1H), 3.55-3.58 (m, 3H),2.58-2.39 (m, 2H), 2.12 (s, 3H), 2.12-2.00 (m, 3H), 1.50-1.37 (m, 2H),0.94-0.78 (m, 9H); ¹³C NMR (300 MHz, D₂O): δ 170.9, 136.5, 114.5, 88.4,70.9, 69.3, 68.8, 68.2, 55.1, 53.0, 42.3, 38.3, 29.9, 27.7, 20.0, 19.9,14.7, 13.3, 13.1; MS (ESPOS): 403.3 [M+H]+.

Example 39 4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Coupling of Boc-protected amino acid to 6b (R²=H, R³=Cl). To a solutionof Boc amino acid 21k (R9=n-propyl, m=1) prepared by general method S,depicted in scheme 21 (131 mg, 0.49 mmol, 1 equiv), 7-Cl MTL 6b (R²=H,R³=Cl) (132 mg, 0.49 mmol, 1 equiv) and HBTU (203 mg, 0.54, 1.1 equiv)in DMF (4.0 mL) at 23° C. was added N,N-diisopropylethylamine (170 μL,0.97 mmol, 2 equiv). The reaction was stirred at 23° C. for 2.5 h thenconcentrated in vacuo to remove DMF. The resulting residue was dissolvedin EtOAc (70 mL), then washed with 1:1 brine: 10% aqueous citric acid(50 mL), saturated aqueous NaHCO₃ (25 mL), brine (30 mL), dried (MgSO₄),filtered and concentrated to give 276 mg of the desired coupled product.This material was used without further purification in the finaldeprotection step: ¹H NMR (300 MHz, CD₃OD) δ 5.41 (br s, 1H), 5.28 (d,J=6.0 Hz, 1H), 4.65-4.52 (m, 1H), 4.46-4.36 (m, 1H), 4.25-4.16 (m, 1H),4.15-3.97 (m, 2H), 3.93-3.74 (m, 2H), 3.55 (dd, J=3.3, 10.2 Hz, 1H),2.62-2.40 (m, 2H), 2.13 (s, 3H), 2.10-1.95 (m, 2H), 1.49 (s, 9H),1.46-1.32 (m, 5H), 0.90 (br t, J=7.2 Hz, 3H); MS (ESPOS): 523.2 [M+H]+.

4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.To a solution of the above Boc-carbamate protected lincosamide (225 mg,0.43 mmol, 1 equiv) in DCE (25 mL) at 23° C. was added H₂O (1.0 mL)followed by TFA (10 mL). The reaction was stirred at 23° C. for 30 minthen treated with toluene (150 mL), then concentrated to a volume of 30μL, then treated with a second portion of toluene (150 mL) andconcentrated to dryness. The crude product was purified via semi-prepHPLC (Waters Nova-Pak® HR C₁₈, 6 μm particle size, 60 Å pore size, 25 mmdiameter×100 mm length, 5-60% acetonitrile in H₂O/0.1% AcOH over 30 min,20 mL/min flow rate) to give 90 mg of pure4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide:¹H NMR (300 MHz, D₂O) δ 5.53 (br s, 1H), 5.39 (br d, J=6.0 Hz, 1H),4.66-4.55 (m, 1H), 4.46 (dd, J=1.2, 10.2 Hz, 1H), 4.33 (d, J=9.9 Hz,1H), 4.19-4.07 (m, 2H), 3.88 (d, J=2.7 Hz, 1H), 3.74 (br s, 2H), 3.66(dd, J=3.0, 10.2 Hz, 1H), 2.70-2.44 (m, 2H), 2.18 (s, 3H), 2.08 (br t,J=7.2 Hz, 3H), 1.52-1.37 (m, 2H), 1.42 (d, J=6.9 Hz, 3H), 0.85 (t, J=6.9Hz, 3H); MS (ESPOS): 423.1 [M+H]+.

Example 40 1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

To a stirred solution of4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide(200 mg, 0.48 mmol, 1 equiv), in anhydrous acetonitrile (3 mL), at roomtemperature, under nitrogen atmosphere, was added triethylamine (0.2 mL,1.44 mmol, 3 equiv) followed by bromoacetamide (80 mg, 0.58 mmol, 1.2equiv). The resulting mixture was stirred at room temperature for 18 h,and evaporated to dryness. The residue obtained was first purified oversilica gel, with an eluant of 7% methanolic-ammonia/dichloromethane. Thedesired fractions were collected, evaporated to dryness, and repurifiedby HPLC (to remove, the side-product from the reaction of the base withbromoacetamide). After lyophilization the desired title compound forexample 40 was obtained (2.0 mg) as a white fluffy powder: HPLC:R_(t)=4.11 min (220.0 nm); ¹H NMR (300 MHz, CD₃OD) δ (rotamers) 5.46 (d,J=5.5, 1), 4.47 (dd, J=3.02, 2.7, 1.1), 4.31-4.25 (m, 3.3), 4.11(d,J=3.02, 1.6), 2.31(s, 3), 1.65-1.52 (m, 9.5), 1.12-1.09 (m,10.3). MS(ESPOS): 476.5 [M+H]+, (ESNEG): 474.5[M−H]−.

Example 41 1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

A stirred solution of crude 4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide(210 mg, 0.50 mmol, 1 equiv) and triethylamine (0.21 mL, 1.51 mmol, 3equiv), in anhydrous acetonitrile (3 mL) was treated withbromoacetonitrile (42 μl, 0.60 mmol, 1.2 equiv), at rt and undernitrogen. The resulting reaction mixture was stirred at rt for 18 h,evaporated to dryness and purified by chromatography over silica gel,with an eluant of 2.5% methanol in dichloromethane. The desiredfractions were pooled, evaporated to dryness, and lyophilized to furnishthe title compound (11.2 mg, 10%) as a fluffy white powder: TLCR_(f)=0.2 (5% methanol in dichloromethane); ¹H NMR (300 MHz, CD₃OD) δ5.44 (d, J=5.49, 1), 4.38-4.23 (m, 4), 2.29 (s, 3), 1.52 (m, 11),1.16-1.09 (m, 12);. MS (ESPOS): 458.5 [M+H]+, MS (ESNEG): 456.5 [M−H]−.

Example 42 1-(1H-Imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

1-(1-Benzyl-1H-imidazol-2-ylmethyl)-4-pent-2-enyl-pyrrolidine-2-carboxylicacid benzyl ester. Boc protected amino acid 7d (R9′=4-pent-2-enyl) (433mg, 1.16 mmol, 1 eq.) was stirred in 4M HCl in dioxane (5 mL) for 2hthen evaporated to dryness. The residue obtained was co-evaporated todryness from DCM (3×20 mL). The crude HCl salt was dissolved in acetone(8 mL) and the resulting solution was treated with diisopropylethylamine(0.61 mL, 3.50 mmol, 3 equiv) followed by1-benzyl-2-(chloromethyl-1H-imidazole (Maybridge) (338 mg, 1.39 mmol,1.2 equiv). The reaction mixture was stirred at room temperature for 48h, and evaporated to dryness. The residue obtained was diluted withEtOAc (200 mL), washed sequentially with 10% citric acid, brine, driedover Na₂SO₄, filtered and evaporated to dryness. The crude materialobtained was purified by silica gel chromatography eluting withCH₂Cl₂/hexanes/MeOH (6:5:1), to furnish the desired N-alkylated product:1-(1-benzyl-1H-imidazol-2-ylmethyl)-4-pent-2-enyl-pyrrolidine-2-carboxylicacid benzyl ester (257 mg, 50%): Rf=0.7 (7:2:1, CH2Cl2/hexanes/MeOH); MS(ESPOS): 444.3 [M+H]+.

1-(1-Benzyl-1H-imidazol-2-ylmethyl)-4-pent-2-enyl-pyrrolidine-2-carboxylicacid. To a stirred solution of1-(1-benzyl-1H-imidazol-2-ylmethyl)-4-pent-2-enyl-pyrrolidine-2-carboxylicacid benzyl ester (257.2 mg, 0.6 mmol, 1 equiv) in a 4:1 THF/H₂O (8 mL),at room temperature, was added lithium hydroxide monohydrate (250 mg,5.96 mmol, 10 equiv). The resulting reaction mixture was stirred at roomtemperature overnight, and evaporated to dryness. The residue obtainedwas dissolved in water (10 mL), and the pH of the resulting solution wasadjusted to between 3 and 4, and extracted with EtOAc (3×100 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and evaporated to dryness, affording the acid product1-(1-Benzyl-1H-imidazol-2-ylmethyl)-4-pent-2-enyl-pyrrolidine-2-carboxylicacid (202 mg, 98%): Rf=0.4 (7:2:1 CH₂Cl₂/hexanes/MeOH), KMnO4visualization stain; MS (ESPOS): 355 [M+H]+; MS (ESNEG): 352 [M−H]−.

1-(1-Benzyl-1H-imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yipropyl]-amide.To a stirred solution of 2b (R2′=H) (96.4 mg, 0.33 mmol, 1 equiv), inanhydrous DMF (1.5 mL), under N₂, at 0° C., was added, triethylamine(0.4 mL, 2.9 mmol, 8.7 equiv), followed by BSTFA (0.4 mL, 1.51 mmol, 4.6equiv). The resulting mixture was stirred at 0° C. for 10 min, then atroom temperature for 30 mins and re-cooled. To the reaction was added asolution of1-(1-benzyl-1H-imidazol-2-ylmethyl)-4-pent-2-enyl-pyrrolidine-2-carboxylicacid (194 mg, 0.55 mmol, 1.7 equiv) followed by solid HATU (261 mg, 0.69mmol, 2.1 equiv). The resulting mixture was stirred at room temperaturefor 3 h and evaporated to dryness. The resulting residue was dissolvedin EtOAc, then washed with 10% aqueous citric acid, saturated aqueousNaHCO3, brine, dried (MgSO4), filtered and concentrated. The crudeper-silylated compound was dissolved in MeOH (60 mL) and treated withDowex H⁺ form resin (250 mg) at room temperature for 45 min, thereaction mixture was filtered, and evaporated to dryness to provide thelincosamide product1-(1-Benzyl-1H-imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.

To an oven dried sealed tube, was added a solution of the above crude1-(1-Benzyl-1H-imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide(280 mg, 0.48 mmol) in anhydrous EtOH (5 mL), 10% Pd on carbon (560 mg)and 1,4-cyclohexadiene (1.5 mL). The reaction vessel was purged with N2,sealed and stirred at room temperature for 18 h. The reaction mixturewas filtered through celite, washed several times with reagent alcohol,and the combined washings and filtrate were evaporated to dryness. Theresulting residue was purified by silica gel chromotography (1:9methanolic ammonia/CH2C12). The desired fractions were evaporated todryness and lyophilized, to furnish the title compound for example 42(29.3 mg, 18%): TLC Rf=0.7 (14% methanolic ammonia/CH2Cl2), KMnO4visualization stain; MS (ESPOS): 499.4 [M+H]+

Example 43 1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

A stirred suspension of 4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide(153 mg, 0.34 mmol, 1 equiv) and ethyl formimidate (Aldrich) (44 mg,0.40 mmol, 1.2 equiv) in dioxane (1 mL) was treated with 1M aqueous NaOH(0.74 mL, 0.74 mmol, 2.2 equiv). After 1 h additional ethyl formimidate(44 mg, 0.40 mmol, 1.2 equiv) was added to the reaction mixture, andstirring was continued for 30 min. The reaction mixture was frozen andlyophilized. The lyophilized powder was purified by columnchromatography to furnish the title compound (8 mg): TLC Rf=0.48CHCl3/MeOH/32% aqueus AcOH (5:3:1); MS (ESPOS): 447.7 [M+H]+, 469.7[M+Na]+; MS (ESNEG): 481.6 [M−H+HCl]−.

Example 44 4-Butyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Boc amino acid 21k (R⁹=n-butyl, R^(9b)=H, m=1) prepared by generalmethod S was coupled to 7-Cl MTL 6b (R²=H, R³=Cl) this material was usedwithout further purification in the final deprotection step.Deprotection and purification to furnish the title compound wasconducted as in previous example 38.

¹H NMR (300 MHz, CD₃OD) δ 5.52 (br s, 1 H), 5.29 (br d, J=5.7 Hz, 1 H),4.63-4.52 (m, 2 H), 4.30 (d, J=9.6 Hz, 1 H), 4.08 (dd, J=5.7 Hz, 1 H),4.00 (dd, J=4.8, 11.4 Hz, 1 H), 3.81 (d, J=2.1 Hz, 1 H), 3.69 (br s, 2H), 3.56 (dd, J=3.3, 10.2 Hz, 1 H), 2.66-2.35 (m, 2 H), 2.20-2.06 (m, 2H), 2.14 (s, 3 H), 1.54-1.28 (m, 7 H), 0.93 (t, J=7.2 Hz, 3 H); MS(ESPOS): 437.2 [M+H]⁺.

Example 45 4-Butyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Boc amino acid 21k (R⁹=n-butyl, R^(9b)=H, m=1) prepared by generalmethod S was coupled to lincosamine 2b (R^(2′)=H) this material was usedwithout further purification in the final deprotection step.Deprotection and purification to furnish the title compound wasconducted as in previous example 38.

¹H NMR (300 MHz, D₂O) δ 5.52 (br s, 1 H), 5.24 (d, J=5.7 Hz, 1 H), 4.23(dd, J=3.6, 10.2 Hz, 1 H), 4.13-4.04 (m, 2 H), 3.95 (dd, J=5.1, 11.1 Hz,1 H), 3.81 (d, J=2.7 Hz, 1 H), 3.68 (br s, 2 H), 3.51 (dd, J=3.3, 10.2Hz, 1 H), 2.59-2.34 (m, 2 H), 2.24-2.06 (m, 3 H), 2.11 (s, 3 H),1.52-1.28 (m, 4 H), 0.98-0.87 (m, 9 H) MS (ESPOS): 417.3 [M+H].

Example 46 5-Propyl-2,3,6,7-tetrahydro-1H-azepine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

To a solution of protected cyclic amino acid 22h (R^(9b)=H, R⁹=propyl)(340 mg, 0.88 mmol) in DMF (3 mL), 6b 7-Cl MTL (R²=H, R³=Cl) (367 mg,0.88 mmol) TEA (332 μL, 1.76 mmol), HBTU (496 mg, 0.97 mmol) was addedat 0° C., stirring at room temperature for overnight. Then solvent wasremoved. Purification was carried by silica gel column chromatography at50-100% EtOAc/Hexane to provide the desired protected lincosamide 13a(R⁹=propyl, R^(9b)=H, m=2, R²=H, R³=Cl, P¹=H, P²=Boc) (575 mg, 90%). MS(ESPOS): 537 [M+1]⁺.

To a solution of Boc protected lincosamide 13a (R⁹=propyl, R^(9b)=H,m=2, R²=H, R³=Cl, P¹=H, P²=Boc) (575 mg, 1.07 mmol) in DCE (15 mL),triethylsilane (0.5 mL), TFA (5 mL), water (0.5 mL) was added, stirringat room temperature for 1.5 hr. Reaction solvents were removed and theresulting residue was purified by chromatography on silica with 5-10%MeOH/DCM to provide the title compound (433 mg, 92%) as a colorlesssolid.

MS (ESPOS): 437 [M+1]⁺.

Example 47 5-Propyl-azepane-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The unsaturated title compound from example 465-Propyl-2,3,6,7-tetrahydro-1H-azepine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide(433 mg, 0.99 mmol) and 10% Pd/C (80 mg), were taken MeOH (10 mL)hydrogenated at 50 psi overnight. The solvent was removed to obtain thecrude material. Purification was carried by silica gel columnchromatography (20% MeOH/DCM) followed by preparative HPLC (generalmethod AC) to furnish isomer 1 R_(t)=18.3 min (10 mg, 2.3%) and isomer 2R_(t)=18.6 min (58 mg, 13.3%).

Isomer 1: ¹H NMR (300 MHz, CD₃OD) δ 5.29 (d, J=5.4, 1), 4.88 (m, 1),4.42 (dd, J=1.8, 10.2, 1), 4.23 (d, J=9.9, 1), 4.10 (dd, J=5.7, 10.2,1), 3.78 (d, J=3.3, 1),3.71 (t, J=6.0, 1), 3.58 (dd, J=3.3, 10.2, 1),3.15 (m, 1), 2.83 (m, 1), 2.13 (m,2), 2.03 (m, 2), 1.86 (m, 2), 1.73 (m,1), 1.50 (m, 4), 1.42 (m, 6), 0.92 (t, J=6.6, 3); MS (ESPOS): 439[M+H]⁺.

Isomer 2: ¹H NMR (300 MHz, CD₃OD) δ 5.30 (d, J=5.7, 1), 5.30 (d, J=5.7,1), 4.61 (m, 2), 4.29 (d, J=9.9, 1), 4.10 (dd, J=5.7, 10.2, 1), 4.00 (m,1), 3.78 (d, J=3.0, 1), 3.58 (dd, J=3.3, 10.2, 1), 3.39 (m, 1), 3.08 (m,1), 2.14 (m, 4), 1.96 (m, 3), 1.59 (m, 3), 1.45 (m, 3), 1.35 (m, 4),0.93 (t, J=6.9, 3); MS (ESPOS): 439 [M+H]⁺.

Example 48 1-Cyclopropyl-5-propyl-azepane-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

5-propyl-azepane-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amideprepared by the methods described in examples 47, 48 (68 mg, 0.16 mmol)in MeOH (2 mL), acetic acid (0.1 mL) was added, followed by1-[(ethyoxycyclopropyl)oxy]trimethylsilane (0.2 mL, 0.96 mmol), sodiumcyanoborohydride (41 mg, 0.64 mmol), and 3 Å molecular sieves, heated toreflux for 3 hrs. Molecular sieves were filtered out and the reactionsolvent was removed to obtain the crude material. Purification wascarried by silica gel column chromatography (10% MeOH/DCM) and HPLC toprovide the title compound (44 mg, 59%). ¹H NMR (300 MHz, CD₃OD) δ 5.20(d, J=5.4, 1), 4.15 (d, J=6.6, 1), 4.08 (dd, J=5.4, 9.9, 1), 3.96 (d,J=3.0, 1), 3.88 (t, J=13.2, 1), 3.62 (m, 1), 3.56 (dd, J=3.3, 10.2, 1),3.14 (m, 1), 2.82 (m, 1), 2.13 (m, 2), 2.05 (s, 3), 1.99-1.30 (m, 10),0.96 (m, 9), 0.51 (m, 4); MS(ESPOS): 459 [M+H]⁺.

Example 491-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-5-propyl-azepane-2-carboxylicacid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound may be prepared by treatment of either isomer 1 orisomer 2 of the title compound from example 46 1 (wherein R²=H, R³=Cl,R⁶=H, R⁹=5-n-propyl, and m=3) with4-Bromomethyl-5-methyl-[1,3]dioxol-2-one (prepared as described in in J.Alexander, et. al. J. Med. Chem, 1996, 39, 480-486.) in DMF in thepresence of sodium carbonate.

Example 502-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-propyl-azepane-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

The title compound may be prepared by treatment of either isomer 1 orisomer 2 of the title compound from example 46 1 (wherein R²=H, R³=Cl,R⁶=H, R⁹=5-n-propyl, and m=3) with carbonic acid5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester 4-nitro-phenyl ester(prepared as described in F. Sakamoto, et. al, Chem. Pharm. Bull. 1984,32 (6), 2241-2348.) in DMF in the presence of potassium bicarbonate.

Example 51 5-Methyl-azepane-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamine 6b 7-Cl MTL (R²=H, R³=Cl) was coupled to cyclic amino acid22f (R⁹=propyl, R^(9b)=H, m=2) prepared by general method T as depictedin general method Z to provide intermediate carbamate 13a (R⁹=Methyl,R^(9b)=H, m=2, R²=H, R³=Cl, P¹=H, P²=Boc) which was deprotected underacidic conditions to provide the crude unsaturated intermediate.Hydrogenation of the unsaturated compound with 10% Pd/C in MeOH at 50psi H₂ provided a crude mixture of position 5 isomers. The two position5 isomers were separated by preparative HPLC.

Isomer 1(low R_(t)): ¹H NMR (300 MHz, CD₃OD) δ 5.30 (d, J=5.7, 1), 4.58(dd, J=6.3, 10.8, 2), 4.30 (d, J=9.9, 1), 4.10 (m, 1), 3.79 (m, 1), 3.58(m, 1), 3.33 (m, 1), 3.13 (m, 1), 2.14 (m, 4), 1.92 (m, 3), 1.55 (m, 1),1.44 (d, J=9.9, 6), 1.00 (d, J=9.9, 3); R_(t): 14.2 min; MS (ESPOS): 412[M+H]⁺.

Isomer 2 (high R_(t)): ¹H NMR (300 MHz, CD₃OD) δ 5.30 (d, J=5.7, 1),4.59 (m, 2), 4.30 (d, J=9.9, 1), 4.10 (m, 1), 3.99 (m, 1), 3.81 (m, 1),3.58 (m, 1), 3.14 (m, 1), 2.14 (m, 4), 1.90 (m, 3), 1.51 (m, 1), 1.44(d, J=9.9, 6), 1.00 (d, J=9.9, 3); R_(t)=14.5 min; MS (ESPOS): 412[M+H]⁺.

Example 52 5-Ethyl-azepane-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamine 6b 7-Cl MTL (R²=H, R³=Cl) was coupled to cyclic amino acid22f (R⁹=propyl, R^(9b)=H, m=2) prepared by general method T as depictedin general method Z to provide intermediate carbamate 13a (R⁹=ethyl,R^(9b)=H, m=2, R²=H, R³=Cl, P¹=H, P² =Boc) which was deprotected underacidic conditions to provide the crude unsaturated intermediate.Hydrogenation of the unsaturated compound with 10% Pd/C in MeOH at 50psi H₂ provided a crude mixture of position 5 isomers. The two position5 isomers were separated by preparative HPLC.

Isomer 1 (low R_(t)): ¹H NMR (300 MHz, CD₃OD) δ 5.30 (d, J=6.0, 1), 4.59(m, 1), 4.49 (m, 1), 4.27 (d, J=9.9, 1), 4.10 (dd, J=6.0, 10.2, 1), 3.92(m, 1), 3.79 (m, 1), 3.55 (m, 1), 2.99 (m, 1), 2.14 (m, 4), 1.79 (m, 3),1.45 (d, J=9.9, 6), 1.38 (m, 3), 0.99 (m, 3); R_(t)=14.6 min MS (ESPOS):425.3 [M+H]⁺.

Isomer 2 (high R_(t)): ¹H NMR (300 MHz, CD₃OD) δ 5.30 (d, J=6.0, 1),4.80 (m, 2), 4.29 (d, J=9.9, 1), 4.10 (dd, J=6.0, 10.2, 1), 3.98 (m, 1),3.80 (d, J=2.7, 1), 3.59 (dd, J=3.0, 10.2, 1), 3.07 (m, 1), 2.14 (m, 4),1.92 (m, 3), 1.52 (m, 1), 1.45 (d, J=9.9, 6), 1.32 (m, 2), 0.93 (m, 3)R_(t): 16 min; MS (ESPOS): 425.3 [M+H]⁺.

Example 53 5-Cyclopropylmethyl-azepane-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound may be prepared by coupling cyclic amino acid 22f(R⁹=cyclopropylmethyl, R^(9b)=H, m=2) prepared by general method T tolincosamine 6b 7-Cl MTL (R²=H, R³=Cl) as depicted in general method Z.Hydrogenation of the unsaturated compound with 10% Pd/C as in example 47provides the title compound as a mixture of position 5 isomers.

Example 54 5-Cyclopropyl-azepane-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound may be prepared by coupling cyclic amino acid 22f(R⁹=cyclopropyl, R^(9b)=H, m=2) prepared by general method T tolincosamine 6b 7-Cl MTL (R²=H, R³=Cl) as depicted in general method Z.Hydrogenation of the unsaturated compound with 10% Pd/C as in example 47provides the title compound as a mixture of position 5 isomers.

Example 55 5-Ethyl-4-methyl-azepane-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound may be prepared by coupling cyclic amino acid 22f(R⁹=ethyl, R^(9b)=methyl, m=2) prepared by general method T tolincosamine 6b 7-Cl MTL (R²=H, R³=Cl) as depicted in general method Z.Hydrogenation of the unsaturated compound with 10% Pd/C as in example 47provides the title compound as a mixture of isomers.

Example 56 4-Ethyl-5-methyl-azepane-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound may be prepared by coupling cyclic amino acid 22f(R⁹=methyl, R^(9b)=ethyl, m=2) prepared by general method T tolincosamine 6b 7-Cl MTL (R²=H, R³=Cl) as depicted in general method Z.Hydrogenation of the unsaturated compound with 10% Pd/C as in example 47provides the title compound as a mixture of isomers.

Example 57 5-Ethyl-6-methyl-azepane-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound may be prepared by coupling cyclic amino acid 22f(R⁹=methyl, R^(9b)=ethyl, m=1) prepared by general method T tolincosamine 6b 7-Cl MTL (R²=H, R³=Cl) as depicted in general method Z.Hydrogenation of the unsaturated compound with 10% Pd/C as in example 47provides the title compound as a mixture of isomers.

Example 58 4-Propyl-azepane-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound may be prepared by coupling cyclic amino acid 22f(R⁹=H, R^(9b)=propyl, m=2) prepared by general method T to lincosamine6b 7-Cl MTL (R²=H, R³=Cl) as depicted in general method Z. Hydrogenationof the unsaturated compound with 10% Pd/C as in example 47 provides thetitle compound as a mixture of position 4 isomers.

Example 59 5-Fluoro-5-propyl-azepane-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound may be prepared by coupling cyclic amino acid 12d(R⁹=propyl, m=2) to lincosamine 6b 7-Cl MTL (R²=H, R³=Cl) as depicted ingeneral method Z.

Example 60 1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid[cyclopropyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide

Lincosamide 23g (R²⁰+R²¹=cyclopropyl, R¹=SMe) was coupled to4-n-Propylhygric acid prepared by the method of Hoeksema, H. et. al.Journal of the American Chemical Society, 1967, 89 2448-2452 was coupledto as depicted in general method Z to provide the title compound.

¹H NMR (300 MHz, D₂O) δ 5.37 (d, J=5.7 Hz, 1 H), 4.26-4.18 (m,2 H), 4.10(dd, J=5.7, 9.9 Hz, 1 H), 3.98 (d, J=3.0 Hz, 1 H), 3.82 (dd, J=6.6, 11.1Hz, 1 H), 3.72 (d, J=8.7 Hz, 1 H), 3.67 (dd, J=3.3, 7.2 Hz, 1 H),2.96-2.83 (m, 1 H), 2.90 (s, 3 H), 2.45-2.16 (m, 3 H), 2.10 (s, 3 H),1.50-1.22 (m, 4 H), 1.10-0.98 (m, 1 H), 0.86 (t, J=7.2 Hz, 3 H),0.67-0.56 (m, 1 H), 0.50-0.40 (m, 1 H), 0.32-0.14 (m, 2 H). MS (ESPOS):403.3 [M+H]; MS (ESNEG): 437.2 [M+Cl].

Example 61 4-Propyl-piperidine-2-carboxylic acid[cyclopropyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide

Lincosamide 23g (R²⁰+R²¹=cyclopropyl, R¹=SMe) was coupled to4-propyl-piperidine-1,2-dicarboxylic acid-1-tert-butyl ester 27b(R⁹=propyl) as depicted in general method Z to provide the titlecompound. Intermediate 13a (R¹=SMe, R²⁰+R²¹=cyclopropyl, R⁹=propyl,P¹=H, P²=carboxylic acid-t-butyl ester, m=2) which was deprotected underacidic conditions to provide the title compound.

¹H NMR (300 MHz, D₂O) δ 5.37 (d, J=5.7 Hz, 1 H), 4.20 (d, J=9.0 Hz, 1H), 4.09 (dd, J=5.7, 10.2 Hz, 1 H), 3.96 (d, J=3.3 Hz, 1 H), 3.85 (dd,J=3.0, 12.9 Hz, 1 H), 3.75-3.65 (m, 2 H), 3.51-3.42 (m, 1 H), 3.07-2.96(m, 1 H), 2.21-2.10 (m, 1 H), 2.10 (s, 3 H), 1.99-1.90 (m, 1 H),1.80-1.65 (m, 1 H), 1.46-1.23 (m, 6 H), 1.11-0.98 (m, 1 H), 0.85 (t,J=6.6 Hz, 3 H), 0.66-0.55 (m, 1 H), 0.50-0.36 (m, 1 H), 0.30-0.12 (m, 2H); MS (ESPOS): 403.3 [M+H]; MS (ESNEG): 437.2 [M+Cl].

Example 62 5-Propyl-azepane-2-carboxylic acid[cyclopropyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide

Lincosamide 23g (R²⁰+R²¹=cyclopropyl, R¹=SMe) was coupled to5-propyl-azepine-1,2-dicarboxylic acid-1-tert-butyl ester as depicted ingeneral coupling method Z to provide the title compound. Intermediate13a (R²⁰+R²¹=cyclopropyl, R⁹=propyl, P¹=H, P²=carboxylic acid-t-butylester, m=3) which was deprotected under acidic conditions to provide thetitle compound.

MS (ESPOS): 451.2 [M+H]⁺.

Example 63 4-Propyl-piperidine-2-carboxylic acid[phenyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide

Lincosamide 23f (R²⁰+R²¹=Ph, R¹=SMe) was prepared as depicted in scheme23.

¹H NMR (300 MHz, CDCl₃) δ 7.41-7.26 (m, 5 H), 6.90 (br d, J=9.6 Hz, 1H), 5.55 (d, J=5.4 Hz, 1 H), 5.49 (dd, J=1.2, 3.3 Hz, 1 H), 5.30-5.23(m, 2 H), 5.17 (dd, J=3.3, 10.8 Hz, 1 H), 4.68 (dd, J=0.9, 8.4 Hz, 1 H),2.08 (s, 3 H), 2.06 (s, 3 H), 1.97 (s, 3 H), 1.62 (s, 3 H); MS (ESPOS):530.0 [M+Na]; MS (ESNEG): 506.0 [M−H].

Lincosamide 23g (R²⁰+R²¹=Ph, R¹=SMe) was prepared as depicted in scheme23.

¹H NMR (300 MHz, CD₃OD) δ 7.40-7.20 (m, 5 H), 5.09 (d, J=5.7 Hz, 1 H),4.16-4.05 (m, 4 H), 3.58 (dd, J=3.3, 10.2 Hz, 1 H), 1.38 (s, 3 H); MS(ESPOS): 286.0 [M+H]; MS (ESNEG): 284.2 [M−H].

Lincosamide 23g (R²⁰+R²¹=Ph, R¹=SMe) was coupled to4-propyl-piperidine-1,2-dicarboxylic acid-1-tert-butyl ester 27b(R⁹=propyl) as depicted in general method Z to provide the titlecompound. Intermediate 13a (R²⁰+R²¹=Ph, R⁹=propyl, P¹=H, P²=carboxylicacid-t-butyl ester, m=2) which was deprotected under acidic conditionsto provide the title compound.

¹H NMR (300 MHz, D₂O) δ 7.46-7.30 (m, 5 H), 5.15 (d, J=5.7 Hz, 1 H),5.11 (d, J=9.9 Hz, 1 H), 4.51 (d, J=10.2 Hz, 1 H), 4.13-4.03 (m, 2 H),3.91 (dd, J=3.0, 12.9 Hz, 1 H), 3.68 (dd, J=3.3, 10.2 Hz, 1 H),3.49-3.40 (m, 1 H), 3.07-2.95 (m, 1 H), 2.10-2.01 (m, 1 H), 1.96-1.86(m, 1 H), 1.78-1.62 (m, 1 H), 1.51 (s, 3 H), 1.36-1.07 (m, 6 H), 0.82(t, J=6.6 Hz, 3 H); MS (ESPOS): 439.3 [M+H]; MS (ESNEG): 473.2 [M+Cl]

Example 64 1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid[phenyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide

Lincosamide 23g (R²⁰+R²¹=Phenyl, R¹=SMe) was coupled to 4-n-depicted ingeneral method Z to provide the title compound.

¹H NMR (300 MHz, D₂O) δ 7.47-7.30 (m, 5 H), 5.15 (d, J=5.7 Hz, 1 H),5.11 (d, J=10.2 Hz, 1 H), 4.50 (d, J=9.9 Hz, 1 H), 4.28 (dd, J=5.4, 9.3Hz, 1 H), 4.11-4.04 (m, 2 H), 3.75 (dd, J=6.0, 11.1 Hz, 1 H), 3.68 (dd,J=3.3, 10.5 Hz, 1 H), 2.91 (s, 3 H), 2.90-2.80 (m, 1 H), 2.45-1.90 (m, 3H), 1.48 (s, 3 H), 1.44-1.10 (m, 4 H), 0.78 (t, J=7.2-Hz, 3 H); MS(ESPOS): 439.3 [M+H]; MS (ESNEG): 473.2 [M+Cl].

Example 65 4-Propyl-piperidine-2-carboxylic acid[cyclopentyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide

Lincosamide 23f (R²⁰+R²¹=cyclopentyl, R¹=SMe) was prepared as depictedin scheme 23.

¹H NMR (300 MHz, CDCl₃) δ 6.29 (br d, J=9.0 Hz, 1 H), 5.63 (d, J=5.7 Hz,1 H), 5.43 (d, J=3.3 Hz, 1 H), 5.25 (dd, J=5.4, 11.1 Hz, 1 H), 5.14 (dd,J=3.3, 11.1 Hz, 1 H), 4.40-4.38 (m, 2 H), 2.30-2.08 (m, 1 H), 2.14 (s, 3H), 2.09 (s, 3 H), 2.08 (s, 3 H), 1.97 (s, 3 H), 1.86-1.48 (m, 6 H),1.27-1.12 (m, 2 H); MS (ESPOS): 522.2 [M+Na]; MS (ESNEG): 498.2 [M−H].

Lincosamide 23g (R²⁰+R²¹=cyclopentyl, R¹=SMe) was prepared as depictedin scheme 23.

¹H NMR (300 MHz, CD₃OD) δ 5.28 (d, J=5.7 Hz, 1 H), 4.16-4.08 (m, 2 H),3.93 (dd, J=0.9, 6.6 Hz, 1 H), 3.54 (dd, J=3.0, 10.2 Hz, 1 H), 2.99 (t,J=6.6 Hz, 1 H), 2.17-2.04 (m, 1 H), 2.07 (s, 3 H), 1.88-1.51 (m, 6 H),1.42-1.26 (m, 2 H)

MS (ESPOS): 278.3 [M+H]; MS (ESNEG): 276.2 [M−H].

Lincosamide 23g (R²⁰+R²¹=cyclopentyl, R¹=SMe) was coupled to4-propyl-piperidine-1,2-dicarboxylic acid-1-tert-butyl ester 27b(R⁹=propyl) as depicted in general method Z to provide the titlecompound. Intermediate 13a (R²⁰+R²¹=cyclopentyl, R⁹=propyl, P¹=H,P²=carboxylic acid-t-butyl ester, m=2) which was deprotected underacidic conditions to provide the title compound.

¹H NMR (300 MHz, D₂O) δ 5.37 (d, J=5.7 Hz, 1 H), 4.23 (dd, J=5.4, 9.3Hz, 1 H), 4.15 (d, J=9.3 Hz, 1 H), 4.09 (dd, J=5.7, 10.5 Hz, 1 H), 3.90(dd, J=3.3, 13.2 Hz, 1 H), 3.63 (dd, J=3.3, 10.5 Hz, 1 H), 3.49 (br d,J=12.6 Hz, 1 H), 3.10-2.98 (m, 1 H), 2.32-2.12 (m, 2 H), 2.13 (s, 3 H),2.10-1.91 (m, 1 H), 1.80-1.04 (m, 16 H), 0.87 (t, J=6.6 Hz, 3 H); MS(ESPOS): 431.3 [M+H]; MS (ESNEG): 465.2 [M+Cl].

Example 66 1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid[cyclopentyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide

Lincosamide 23g (R²⁰+R²¹=cyclopentyl, R¹=SMe) was coupled to4-n-Propylhygric acid as depicted in general method Z to provide thetitle compound.

¹H NMR (300 MHz, D₂O) δ 5.35 (d, J=6.0 Hz, 1 H), 4.31-4.22 (m, 2 H),4.16 (d, J=9.0 Hz, 1 H), 4.09 (dd, J=5.7, 10.5 Hz, 1 H), 3.94 (d, J=3.0Hz, 1 H), 3.85 (dd, J=6.3, 11.1 Hz, 1 H), 3.63 (dd, J=3.0, 10.5 Hz, 1H), 2.95-2.85 (m, 1 H), 2.93 (s, 3 H), 2.45-2.13 (m, 3 H), 2.13 (s, 3H), 1.84-1.03 (m, 13 H), 0.87 (t, J=7.2 Hz, 3 H); MS (ESPOS): 431.3[M+H]; MS (ESNEG): 465.2 [M+Cl].

Example 67 5-Propyl-azepane-2-carboxylic acid[cyclopentyl-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide

Lincosamide 23g (R²⁰+R²¹=cyclopentyl, R¹=SMe) was coupled to5-propyl-azepine-1,2-dicarboxylic acid-1-tert-butyl ester as depicted ingeneral method Z to provide the title compound. Intermediate 13a(R¹=SMe, R²⁰+R²¹=cyclopentyl, R⁹=propyl, P¹=H, P²=carboxylicacid-t-butyl ester, m=3) which was deprotected under acidic conditionsto provide the title compound.

¹H NMR (300 MHz, D₂O) δ 5.33 (d, J=5.7 Hz, 1 H), 4.24 (dd, J=4.8, 9.0Hz, 1 H), 4.19-4.11 (m, 2 H), 4.07 (dd, J=5.7, 10.5 Hz, 1 H), 3.90 (d,J=3.0 Hz, 1 H), 3.62 (dd, J=3.3, 10.5 Hz, 1 H), 3.46 (dd, J=4.2, 13.8Hz, 1 H), 3.19-3.08 (m, 1 H), 2.36-2.09 (m, 3 H), 2.12 (s, 3 H),2.08-1.81 (m, 2 H), 1.80-1.40 (m, 8 H), 1.36-1.01 (m, 7 H), 0.83 (t,J=6.6 Hz, 3 H); MS (ESPOS): 445.2 [M+H]; MS (ESNEG): 479.0 [M+Cl].

Example 68 1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid[1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-but-3-enyl]-amide

Lincosamide 23f (R²⁰=vinyl, R²¹=H, R¹=SMe) was prepared as depicted inscheme 23.

¹H NMR (300 MHz, CDCl₃) δ 6.31 (br d, J=9.3 Hz, 1 H), 5.80-5.62 (m, 1H), 5.64 (d, J=5.4Hz, 1 H), 5.41 (dd, J=0.9, 3.0Hz, 1 H), 5.26 (dd,J=5.4, 10.8 Hz, 1 H), 5.23-5.10 (m, 3 H), 4.42-4.25 (m, 2 H), 3.56-2.44(m, 1 H), 2.35-2.23 (m, 1 H), 2.14 (s, 3 H), 2.09 (s, 3 H), 2.08 (s, 3H), 1.97 (m, 3 H); MS (ESNEG): 470.0 [M−H].

Lincosamide 23g (R²⁰=vinyl, R²¹=H, R¹=SMe) was prepared as depicted inscheme 23.

¹H NMR (300 MHz, CD₃OD) δ 5.94-5.78 (m, 1 H), 5.27 (d, J=5.7 Hz, 1 H),5.20-5.10(m, 2 H),4.09 (dd, J=5.7, 10.2Hz, 1 H), 4.04 (dd, J=1.5, 3.3Hz, 1 H), 3.82 (dd, J=0.9, 8.1 Hz, 1 H), 3.57 (dd, J=3.3, 9.9 Hz, 1 H),3.13 (dt, J=3.9, 8.4 Hz, 1 H), 2.57-2.47 (m, 1 H), 2.14-2.02 (m, 1 H),2.07 (s, 3 H); MS (ESPOS): 272.0 [M+Na]; MS (ESNEG): 248.2 [M−H].

Lincosamide 23g (R²⁰=vinyl, R²¹=H, R¹=SMe) was coupled to4-n-Propylhygric acid as depicted in general method Z to provide thetitle compound. ¹H NMR (300 MHz, D₂O) δ 5.84-5.68 (m, 1 H), 5.37 (d,J=5.7 Hz, 1 H), 5.16-5.07 (m, 2 H), 4.28-4.18 (m, 2 H), 4.14-4.07 (m, 2H), 3.93 (d, J=3.3 Hz, 1 H), 3.82 (dd, J=6.3, 11.1 Hz, 1 H), 3.66 (dd,J=3.3, 10.5 Hz, 1 H), 2.91-2.83 (m, 1 H), 2.91 (s, 3 H), 2.67-2.58 (m, 1H), 2.40-2.10 (m, 4 H), 2.11 (s, 3 H), 1.52-1.22 (m, 4 H), 0.87 (t,J=7.2 Hz, 3 H); MS (ESPOS): 403.3 [M+H]; MS (ESNEG): 437.0 [M+Cl].

Example 69 4-Propyl-piperidine-2-carboxylic acid[1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-but-3-enyl]-amide

Lincosamide 23g (R²⁰=vinyl, R²¹=H, R¹=SMe) was coupled to4-propyl-piperidine-1,2-dicarboxylic acid-1-tert-butyl ester 27b(R⁹=propyl) as depicted in general method Z to provide the titlecompound. Intermediate 13a (R²⁰=vinyl, R²¹=H, R¹=SMe, R⁹=propyl, P¹=H,P²=carboxylic acid-t-butyl ester, m=2) which was deprotected underacidic conditions to provide the title compound.

¹H NMR (300 MHz, D₂O) δ 5.82-5.66 (m, 1 H), 5.37 (d, J=5.7 Hz, 1 H),5.16-5.07 (m, 2 H), 4.24-4.05 (m, 3 H), 3.92 (d, J=3.3 Hz, 1 H), 3.85(dd, J=3.3, 12.9 Hz, 1 H), 3.66 (dd, J=3.3, 10.5 Hz, 1 H), 3.47 (br d,J=12.3 Hz, 1 H), 3.08-2.96 (m, 1 H), 2.66-2.56 (m, 1 H), 2.22-2.10 (m, 2H), 2.11 (s, 3 H), 1.99-1.89 (m, 1 H), 1.80-1.64 (m, 1 H), 1.41-1.22 (m,6 H), 0.87 (t, J=6.6 Hz, 3 H); MS (ESPOS): 403.3 [M+H]; MS (ESNEG):437.2 [M+Cl].

Example 70 5-Propyl-azepane-2-carboxylic acid[1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-butyl]-amide

The title compound was be prepared by coupling cyclic amino acid 22f(R⁹=propyl, R^(9b)=H, m=2) prepared by general method T to lincosamine23 g (R²⁰=ethyl, R²¹=H, R¹=SMe) as depicted in general method Z.Hydrogenation of the unsaturated intermediate provided the titlecompound.

¹H NMR (300 MHz, D₂O) δ 5.34 (d, J=5.7 Hz, 1 H), 4.16-4.04 (m, 3 H),4.01 (d, J=9.3 Hz, 1 H), 3.89 (d, J=3.3 Hz, 1 H), 3.64 (dd, J=3.3, 10.5Hz, 1 H), 3.45 (dd, J=5.1, 13.2 Hz, 1 H), 3.13 (t, J=12.0 Hz, 1 H),2.20-1.16 (m, 15 H), 2.08 (s, 3 H), 0.86 (t, J=7.5 Hz, 3 H), 0.83 (t,J=6.9 Hz, 3 H); MS (ESPOS): 419.0 [M+H]; MS (ESNEG): 453.2 [M+Cl].

Example 71 4-Propyl-piperidine-2-carboxylic acid[1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-butyl]-amide

Hydrogenation of the title compound from example 69 provided the titlecompound.

¹H NMR (300 MHz, D₂O) δ 5.34 (d, J=6.0Hz, 1 H), 4.14-4.04 (m, 2 H), 4.00(d, J=9.3 Hz, 1 H), 3.91-3.83 (m, 2 H), 3.64 (dd, J=3.3, 10.5 Hz, 1 H),3.51-3.43 (m, 1 H), 3.08-2.96 (m, 1 H), 2.22-2.13 (m, 1 H), 2.07 (s, 3H), 1.99-1.89 (m, 1 H), 1.83-1.65 (m, 2 H), 1.48-1.13 (m, 9 H), 0.85 (t,J=7.5 Hz, 6 H); MS (ESPOS): 405.4 [M+H]; MS (ESNEG): 439.2 [M+Cl].

Example 72 1-Methyl4-propyl-pyrrolidine-2-carboxylic acid[1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-butyl]-amide

Hydrogenation of the title compound from example 68 provided the titlecompound.

¹H NMR (300 MHz, D₂O) δ 5.36 (d, J=6.0 Hz, 1 H), 4.28-4.03 (m, 4 H),3.93 (d, J=3.0 Hz, 1 H), 3.85 (dd, J=6.9, 11.1 Hz, 1 H), 3.66 (dd,J=3.0, 10.2 Hz, 1 H), 2.95-2.85 (m, 1 H), 2.93 (s, 3 H), 2.47-2.19 (m, 3H), 2.10 (s, 3 H), 1.86-1.70 (m, 1 H), 1.54-1.16 (m, 7 H), 0.87 (t,J=6.9 Hz, 6 H); MS (ESPOS): 405.4 [M+H]; MS (ESNEG): 439.2 [M+Cl].

Example 73 1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid[(4-chloro-phenyl)-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide

Lincosamide 23f (R²⁰+R²¹=4-chlorophenyl, R¹=SMe) was prepared asdepicted in scheme 23.

¹H NMR (300 MHz, CDCl₃) □ 7.34 (d, J=8.4 Hz, 2 H), 7.25 (d, J=8.4 Hz, 2H), 7.16 (br d, J=9.0 Hz, 1 H), 5.55 (d, J=5.4 Hz, 1 H), 5.50 (d, J=2.1Hz, 1 H), 5.30-5.13 (m, 3 H), 4.66 (d, J=8.7 Hz, 1 H), 2.09 (s, 3 H),2.07 (s, 3 H), 1.98 (s, 3 H), 1.65 (s, 3 H); MS (ESPOS): 563.9 [M+Na];MS (ESNEG): 539.8 [M−H].

Lincosamide 23g (R²⁰+R²¹=4-chlorophenyl, R¹=SMe) was prepared asdepicted in scheme 23.

¹H NMR (300 MHz, CD₃OD) □ 7.37 (d, J=8.4 Hz, 2 H), 7.31 (d, J=9.0 Hz, 2H), 5.09 (d, J=6.0 Hz, 1 H), 4.13-4.03 (m, 4 H), 3.58 (dd, J=3.3, 10.2Hz, 1 H), 1.41 (s, 3 H); MS (ESPOS): 320.0 [M+H]; MS (ESNEG): 354.0[M+Cl].

Lincosamide 23g (R²⁰+R²¹=4-chlorophenyl, R¹=SMe) was coupled to4-n-Propylhygric acid as depicted in general method Z to provide thetitle compound.

¹H NMR (300 MHz, D₂O) □ 7.43 (d, J=8.1 Hz, 2 H), 7.36 (d, J=8.4 Hz, 2H), 5.18 (d, J=6.0Hz, 1 H), 5.12 (d, J=10.2 Hz, 1 H), 4.48 (d, J=9.9 Hz,1 H), 4.29 (dd, J=5.4, 9.0 Hz, 1 H), 4.14-4.05 (m, 2 H), 3.78 (dd,J=5.7, 10.8 Hz, 1 H), 3.70 (dd, J=3.3, 10.2 Hz, 1 H), 2.92 (s, 3 H),2.87 (t, J=10.8 Hz, 1 H), 2.26-2.11 (m, 2 H), 2.07-1.94 (m, 1 H), 1.52(s, 3 H), 1.46-1.12 (m, 4 H), 0.81 (t, J=7.2 Hz, 3 H); MS (ESPOS): 473.2[M+H]; MS (ESNEG): 507.2 [M+Cl].

Example 74 4-Propyl-piperidine-2-carboxylic acid[(4-chloro-phenyl)-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide

Lincosamide 23g (R²⁰+R²¹=4-chlorophenyl, R¹=SMe) was coupled to 27b(R⁹=propyl) as depicted in general method Z to provide the titlecompound.

¹H NMR (300 MHz, CD₃OD) δ 7.35 (s, 4 H), 5.20 (d, J=9.6 Hz, 1 H), 5.14(d, J=6.0 Hz, 1 H), 4.36 (d, J=9.3 Hz, 1 H), 4.10 (dd, J=5.7, 10.2 Hz, 1H), 3.99 (d, J=3.0 Hz, 1 H), 3.89 (dd, J=3.0, 12.6 Hz, 1 H), 3.59 (dd,J=3.3, 10.2 Hz, 1 H), 3.45-3.36 (m, 1 H), 3.04 (dt, J=3.3, 13.2 Hz, 1H), 2.24-2.14 (m, 1 H), 1.98-1.88 (m, 1 H), 1.81-1.66 (m, 1 H), 1.52 (s,3 H), 1.46-1.13 (m, 6 H), 0.94 (t, J=7.2 Hz, 3 H); MS (ESPOS): 473.2[M+H]; MS (ESNEG): 507.2 [M+Cl].

Example 75 1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamide 23f (R²⁰=methyl, R²¹=methyl, R¹=isopropyl sulfanyl) wasprepared as depicted in scheme 23.

¹H NMR (300 MHz, CDCl₃) δ 6.10 (br d, J=10.5 Hz, 1 H), 5.79 (d, J=5.4Hz, 1 H), 5.36 (dd, J=1.2, 3.3 Hz, 1 H), 5.20 (dd, J=5.7, 11.1 Hz, 1 H),5.09 (dd, J=3.3, 10.8 Hz, 1 H), 4.36 (dd, J=0.9, 9.9 Hz, 1 H), 4.26 (dt,J=3.0, 10.2 Hz, 1 H), 3.04-2.90 (m, 1 H), 2.13 (s, 3 H), 2.07 (s, 3 H),1.97 (s, 3 H), 1.29 (d, J=4.8 Hz, 3 H), 1.27 (d, J=5.1 Hz, 3 H), 0.91(d, J=6.9 Hz, 3 H), 0.86 (d, J=6.9 Hz, 3 H)

MS (ESPOS): 524.0 [M+Na]

MS (ESNEG): 500.0 [M−H]

Lincosamide 23g (R²⁰=methyl, R²¹=methyl, R¹=isopropyl sulfanyl) wasprepared as depicted in scheme 23.

¹H NMR (300 MHz, CD₃OD) δ 5.36 (d, J=6.0 Hz, 1 H), 4.05 (dd, J=5.7, 10.2Hz, 1 H), 4.01 (dd, J=1.5, 3.3 Hz, 1 H), 3.95 (dd, J=1.2, 8.7 Hz, 1 H),3.48 (dd, J=3.3, 10.5 Hz, 1 H), 3.04-2.93 (m, 1 H), 2.89 (dd, J=3.6, 8.4Hz, 1 H), 2.07-1.95 (m, 1 H), 1.30 (d, J=6.9 Hz, 3 H), 1.26 (d, J=6.9Hz, 3 H), 0.98 (d, J=6.9 Hz, 3 H), 0.87 (d, J=6.6 Hz, 3 H); MS (ESPOS):280.0 [M+H]; MS (ESNEG): 278.2 [M−H]

Lincosamide 23g (R²⁰=methyl, R²¹=methyl, R¹=isopropyl sulfanyl) wascoupled to 4-n-Propylhygric acid as depicted in general method Z toprovide the title compound.

¹H NMR (300 MHz, D₂O) δ 5.47 (d, J=6.0 Hz, 1 H), 4.25 (br t, J=7.2 Hz, 1H), 4.16 (br s,2 H), 4.07 (dd, J=5.7, 10.5 Hz, 1 H), 3.83 (dd, J=8.1,11.4 Hz, 2 H), 3.56 (dd, J=3.0, 10.5 Hz, 1 H), 3.11-2.99 (m, 1 H), 2.91(s, 3 H), 2.88 (br t, J=11.1 Hz, 1 H), 2.45-2.20 (m, 3 H), 2.15-2.00 (m,1 H), 1.50-1.37 (m, 2 H), 1.36-1.23 (m, 8 H), 0.90-0.80 (m, 9 H); MS(ESPOS): 433.4 [M+H]; MS (ESNEG): 467.2 [M+Cl]

Example 76 4-Propyl-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamide 23g (R²⁰=methyl, R²¹=methyl, R¹=isopropyl sulfanyl) wascoupled to 4-propyl-piperidine-1,2-dicarboxylic acid-1-tert-butyl ester27b (R⁹=propyl) as depicted in general method Z to provide the titlecompound. Intermediate 13a (R¹=isopropyl sulfanyl, R²⁰=methyl,R²¹=methyl, R⁹=propyl, P¹=H, P²=carboxylic acid-t-butyl ester, m=2)which was deprotected under acidic conditions to provide the titlecompound.

¹H NMR (300 MHz, D₂O) δ 5.47 (d, J=6.0 Hz, 1 H), 4.14 (br s, 2 H), 4.07(dd, J=6.0, 10.5 Hz, 1 H), 3.89 (dd, J=3.0, 12.6 Hz, 1 H), 3.83 (d,J=3.3 Hz, 1 H), 3.56 (dd, J=3.3, 10.5 Hz, 1 H), 3.47 (br d, J=13.5 Hz, 1H), 3.12-2.96 (m, 2 H), 2.25-1.90 (m, 3 H), 1.80-1.66 (m, 1 H),1.50-1.22 (m, 12 H), 0.90-0.79 (m, 9 H); MS (ESPOS): 433.4 [M+H]; MS(ESNEG): 467.2 [M+Cl].

Example 77 1-Methyl-4-propyl-pyrrolidine-2-carboxylic acid[1-(6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide

Lincosamide 23f (R²⁰=methyl, R²¹=methyl R¹=tert-butyl sulfanyl) wasprepared as depicted in scheme 23.

¹H NMR (300 MHz, CDCl₃) δ 6.08 (br d, J=9.3 Hz, 1 H), 5.81 (d, J=5.7Hz,1 H), 5.34 (d, J=3.0 Hz, 1 H), 5.19 (dd, J=5.7, 11.1 Hz, 1 H), 5.01 (dd,J=3.3, 11.1 Hz, 1 H), 4.34-4.18 (m, 2 H), 2.20-2.05 (m, 1 H), 2.13 (s, 3H), 2.07 (s, 3 H), 1.97 (s, 3 H), 1.32 (m, 9 H), 0.89 (t, J=6.6 Hz, 6H); MS (ESPOS): 538.0 [M+Na]; MS (ESNEG): 514.2 [M−H].

Lincosamide 23g (R²⁰=methyl, R²¹=methyl, R¹=tert-butyl sulfanyl) wasprepared as depicted in scheme 23.

¹H NMR (300 MHz, CD₃OD) δ 5.39 (d, J=5.7 Hz, 1 H), 4.05 (dd, J=6.0, 10.8Hz, 1 H), 4.01 (dd, J=1.2, 3.3 Hz, 1 H), 3.90 (dd, J=1.5, 8.7 Hz, 1 H),3.39 (dd, J=3.3, 10.5 Hz, 1 H), 2.88 (dd, J=3.6, 8.1 Hz, 1 H), 2.08-1.95(m, 1 H), 1.36 (s, 9 H), 0.98 (d, J=6.9 Hz, 3 H), 0.89 (d, J=6.9 Hz, 3H); MS (ESPOS): 294.0 [M+H]; MS (ESNEG): 292.2 [M−H]

Lincosamide 23g (R²=isopropyl, R¹=tert-butyl sulfanyl) was coupled to4-n-Propylhygric acid as depicted in general method Z to provide thetitle compound.

¹H NMR (300 MHz, D₂O) δ 5.50 (d, J=5.7 Hz, 1 H), 4.26 (br t, J=7.5 Hz, 1H), 4.15 (br s, 2 H), 4.08 (dd, J=5.7, 10.5 Hz, 1 H), 3.90-3.82 (m, 2H), 3.50 (dd, J=3.0, 10.8 Hz, 1 H), 2.93 (s, 3 H), 2.91 (br t, J=11.1Hz, 1 H), 2.48-2.25 (m, 3 H), 2.16-2.04 (m, 1 H), 1.52-1.26 (m, 4 H),1.37 (m, 9 H), 0.88 (t, J=6.9 Hz, 9 H); MS (ESPOS): 447.4 [M+H]; MS(ESNEG): 481.2 [M+Cl].

Example 78 4-Propyl-piperidine-2-carboxylic acid[1-(6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide

Lincosamide 23g (R²⁰=methyl, R²¹=methyl, R¹=tert-butyl sulfanyl) wascoupled to 4-propyl-piperidine-1,2-dicarboxylic acid-1-tert-butyl ester27b (R⁹=propyl) as depicted in general method Z to provide the titlecompound. Intermediate 13a (R¹=tert-butyl sulfanyl, R²⁰=methyl,R²¹=methyl, R⁹=propyl, P¹=H, P²=carboxylic acid-t-butyl ester, m=2)which was deprotected under acidic conditions to provide the titlecompound.

¹H NMR (300 MHz, D₂O) δ 5.50 (d, J=5.7 Hz, 1 H), 4.13 (br s, 2 H), 4.08(dd, J=5.7, 10.5 Hz, 1 H), 3.92 (dd, J=3.0, 12.6 Hz, 1 H), 3.85 (d,J=3.3 Hz, 1 H), 3.51 (dd, J=3.0, 10.5 Hz, 2 H), 3.06 (br t, J=10.8 Hz, 1H), 2.28-2.19 (m, 1 H), 2.16-1.93 (m, 2 H), 1.85-1.69 (m, 1 H),1.54-1.27 (m, 6 H), 1.38 (s, 9 H), 0.94-0.83 (m, 9 H); MS(ESPOS): 447.4[M+H]; MS (ESNEG): 481.0 [M+Cl].

Example 79 4-(2-Cyclopropyl-ethyl)-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

To a stirred suspension of 11b (0.5 g, 1.9 mmol, 1 equiv),triphenylphosphine (39.9 mg, 0.15 mmol, 0.08 equiv), copper (I) iodide(28.9 mg, 0.15 mmol, 0.08 equiv), palladium acetate (17 mg, 0.076 mmol,0.04 equiv) in triethylamine (7 mL) under dry nitrogen, was addedcyclopropyl acetylene (Aldrich) (0.25 g, 3.8 mmol, 2 equiv). The mixturewas stirred at rt overnight. The solvent was removed under vacuum togive a dark residue. The residue was purified by column chromatographyto give 11c (R^(9′)=2-cyclopropyl-eth-1-ynyl) (0.39 g; 100%) as a yellowoil.

¹H NMR (300 MHz, CDCl₃) δ 8.65-8.56 (m, 1), 8.06-7.99 (m, 1), 7.40-7.32(m, 1), 3.98 (s, 3), 1.50-1.40 (m, 1), 0.96-0.81 (m, 4); MS (ESPOS):202.0 [M+H]⁺.

To a solution of 11c (R^(9′)=2-cyclopropyl-eth-1-ynyl) (0.39 g, 1.9mmol) in methanol (15 mL) was added 10% palladium on carbon (0.2 g). Themixture was purged and charged with hydrogen (1 atm) and stirred at rtovernight. The palladium was removed by filtration and the filtrate wasconcentrated to give 4-(2-cyclopropylethyl)-pyridine-2-carboxylic acidmethyl ester (0.38 g, 97%) as a yellow oil. (intermediate not shown)

¹H NMR (300 MHz, CDCl₃) δ 8.60 (d, J=4.5, 1), 8.00-7.96 (m, 1),7.34-7.29(m, 1), 3.99 (s, 3), 2.78 (t, J=7.6, 2), 1.58-1.49 (m, 2),0.71-0.59 (m, 1), 0.47-0.38 (m, 2), 0.06-0.02 (m, 2); MS (ESPOS): 228.2[M+Na]⁺.

To a mixture of 4-(2-cyclopropylethyl)-pyridine-2-carboxylic acid methylester (0.38 g) in MeOH (8 mL) and water (8 mL) were added concentratedHCl (158 μL) and platinum oxide (0.2 g). The mixture was purged andcharged with hydrogen (1 atm) and stirred overnight. The platinum oxidewas removed by filtration and the filtrate was evaporated to give alight yellow solid 11d (R⁹=2-cyclopropylethyl) which was used withoutfurther purrification.

To the above crude residue 11d (R⁹=2-cyclopropylethyl) was added 2N NaOH(3.8 mL) and t-butylalcohol (2 mL). The reaction mixture was stirred atrt for 2 h, di-t-butyl dicarbonate (0.62 g, 2.85 mmol) was then addedand the mixture stirred overnight. The solvent was removed under vacuumand the resulting residue was diluted with water, then washed withether. The aqueous layer was acidified with 2N HCl to pH=2.0, extractedtwice with ethyl acetate. The combined organic layers were dried overMgSO₄ and concentrated to give4-(2-cyclopropylethyl)-piperidine-1,2-dicarboxylic acid 1-tert-butylester 11f (P=Boc, R⁹=2-cyclopropylethyl) (0.42 g, 77%) as a clear syrup.

MS (ESPOS): 320.3 [M+Na]⁺; MS (ESNEG): 296.2 [M−H]⁻.

Lincosamide 6b (R²=H, R³=Cl) was coupled to4-(2-cyclopropylethyl)-piperidine-1,2-dicarboxylic acid 1-tert-butylester 11f (P=Boc, R⁹=2-cyclopropylethyl) as depicted in general method Zto provide the title compound. Intermediate 13a (R²⁰=methyl, R²¹=methyl,R⁹=propyl, P²=H, P²=carboxylic acid-t-butyl ester, m=2) which wasdeprotected under acidic conditions to provide the title compound.

MS (ESPOS): 451.3 [M+H]⁺.

Example 80 4-Cyclopropylmethyl-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-Cyclopropylmethylpyridine-2-carboxylic acid, compound 10b(R⁹=cyclopropylmethyl), was made by employing general method O using thestarting material 4-Cyclopropylmethylpyridine prepared by alkylation of4-picoline with cyclopropylbromide by the method described by Osuch etal, Journal of the American Chemical Society, 1955, 78, 1723. Themodified method is shown below.

To a −78° C. solution of 4-picoline (1.1 g, 11.8 mmol) in THF (5 mL) wasadded a solution of LDA 2M in THF/heptane/ethylbenzene (Aldrich) (5.9mL, 11.8 mmol) the resulting reaction mixture was stirred at −78° C. for3 h then −40° C. for 1 h. Then cyclopropyl bromide (1.43 g, 11.8 mmol)was added at −78° C., let it warm up to room temperature and stirred atroom temperature for 1 h. To the reaction mixture was added saturatedaqueous NH₄Cl (10 mL) the aqueous phase was extracted with EtOAc (10×2mL) and the combined organic extracts dried over Na₂SO₄. The solvent wasremoved and the product 4-Cyclopropylmethylpyridine (0.5 g, 31%) wasobtained and used without further purification.

Lincosamide 6b (R²=H, R³=Cl) was coupled to4-cyclopropylmethylpyridine-2-carboxylic acid 10b (R⁹=cyclopropylmethyl)as in general method AA to provide intermediate 13b (R¹=SMe, R²=Me,R³=H, R⁹=cyclobutyl-ethyl, P¹=H) which was reduced by catalytichydrogenation to the title compound.

MS (ESPOS): 437.2 [M]⁺.

Example 81 4-(2-Cyclobutyl-ethyl)-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-(Cyclobutyl-ethyl)-pyridine-2-carboxylic acid, compound 10b(R⁹=cyclobutyl-ethyl), was made by employing general Method O using thestarting material 4-(Cyclobutyl-ethyl)-pyridine prepared by alkylationof 4-picoline with bromomethylcyclobutane as described in example 80.

Lincosamide 6b (R²=H, R³=Cl) was coupled to4-(cyclobutyl-ethyl)-pyridine-2-carboxylic acid 10b(R⁹=cyclobutyl-ethyl) as in general coupling method AA to provideintermediate 13b (R¹=SMe, R²=Me, R³=H, R⁹=cyclobutyl-ethyl, P¹=H) whichwas reduced by catalytic hydrogenation to the title compound.

MS (ESPOS): 465.2 [M]⁺.

Example 82 4-Cyclobutylmethyl-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-Cyclobutylmethylpyridine-2-carboxylic acid, compound 10b(R⁹=4-cyclobutylmethyl) was made by employing general Method O using thestarting material 4-cyclobutylmethylpyridine prepared by alkylation of4-picoline with cyclobutyl bromide as described in example 80.

Lincosamine 6b (R²=H, R³=Cl) was coupled to4-cyclobutylmethylpyridine-2-carboxylic acid, compound 10b(R⁹=4-cyclobutylmethyl) as in general coupling method AA to provideintermediate 13b (R¹=SMe, R²=Me, R³=H, R⁹=cyclobutylethyl P¹=H) whichwas reduced by catalytic hydrogenation to the title compound.

MS (ESPOS): 451.2 [M+H]⁺.

Example 83 4-Cyclopropylmethyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The protected amino acid intermediate(2S,4R)-4-cyclopropylmethyl-pyrrolidine-1,2-dicarboxylicacid-1-tert-butyl ester was prepared by the synthetic sequence describedby Goodman et al. Journal of Organic Chemistry, 2003, 68, 3923 usingcyclopropylmethyl triphenylphosphonium bromide (Aldrich) as the startingmaterial in the wittig olefination step.

Lincosamine 6b (R²=H, R³=Cl) was coupled to(2S,4R)-4-cyclopropyhnethyl-pyrrolidine-1,2-dicarboxylicacid-1-tert-butyl ester as depicted in general coupling scheme 11 toprovide intermediate 13a (R¹=SMe, R²=Me, R⁹=cyclopropylmethyl, P¹=H,P²=carboxylic acid-t-butyl ester, m=1) which was deprotected underacidic conditions to provide the title compound.

MS (ESPOS): 423.2 [M+H]⁺.

Example 84 4-(2-Cyclobutylidene-ethyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Amino acid intermediate(2S,4R)-4-(2-cyclobutylidene-ethyl)-pyrrolidine-1,2-dicarboxylicacid-1-tert-butyl ester was prepared by general method K by alkylationof pyroglutamic acid ester 7a with (2-bromo-ethylidene)-cyclobutane. Theallylic halide (2-bromo-ethylidene)-cyclobutane starting material wasprepared from cyclobutanone in two steps as disclosed in U.S. Pat. No.3,711,555.

Lincosamine 2b (R¹=SMe, R²=Me) was coupled to protected amino acid 8c(R^(9′)=2-cyclobutylidene-ethyl) to provide intermediate carbamate 13a(R¹=SMe, R²=Me, R⁹=2-cyclobutylidene-ethyl, P¹=H, P²=Boc, m=1) which wasdeprotected under acidic conditions to provide the title compound.

MS (ESPOS): 429.1 [M+H]⁺.

Example 85 4-(2-Cyclobutylidene-ethyl)-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Amino acid intermediate(2S,4R)-4-(2-cyclobutylidene-ethyl)-pyrrolidine-1,2-dicarboxylicacid-1-tert-butyl ester was prepared by general method K by alkylationof pyroglutamic acid ester 7a with (2-bromo-ethylidene)-cyclobutane. Theallylic halide (2-bromo-ethylidene)-cyclobutane starting material wasprepared from cyclobutanone in two steps as disclosed in U.S. Pat. No.3,711,555.

Lincosamine 6b (R²=H, R³=Cl) was coupled to protected amino acid 8c(R^(9′)=2-cyclobutylidene-ethyl) to provide intermediate carbamate 13a(R¹=SMe, R²=Me, R^(9′)=2-cyclobutylidene-ethyl, P¹=H, P²=Boc, m=1) whichwas deprotected under acidic conditions to provide the title compound.

MS (ESPOS): 450.1 [M+H]⁺.

Example 86 4-(2-Cyclobutyl-ethyl)-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Amino acid intermediate(2S,4R)-4-(2-cyclobutyl-ethyl)-pyrrolidine-1,2-dicarboxylicacid-1-tert-butyl ester was prepared by general method K by alkylationof pyroglutamic acid ester 7a with (2-bromo-ethylidene)-cyclobutane. Theallylic halide (2-bromo-ethylidene)-cyclobutane starting material wasprepared from cyclobutanone in two steps as disclosed in U.S. Pat. No.3,711,555.

Lincosamine 6b (R²=H, R³=Cl) was coupled to protected amino acid 7d(R⁹=2-cyclobutyl-ethyl) to provide intermediate carbamate 13a (R¹=SMe,R²=Me, R⁹=cyclobutyl-ethyl, P¹=H, P²=Boc, m=1) which was deprotectedunder acidic conditions to provide the title compound.

MS (ESPOS): 451.2 [M]⁺.

Example 87 4-(2-Cyclopropyl-ethyl)-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamine 2b (R¹=SMe, R²=Me) was coupled to protected amino acid 8c(R⁹=2-cyclopropyl-ethyl) prepared by general method M to provideintermediate carbamate 13a (R¹=SMe, R²=Me, R⁹=cyclopropyl-ethyl, P¹=H,P²=carboxylic acid-t-butyl ester, m=1) which was deprotected underacidic conditions to provide the title compound.

MS (ESPOS): 437.2 [M+H]⁺.

Example 884-Fluoro-1-(2-hydroxy-ethyl)-4-propyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-=methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide18a (Example 32) was treated with ethylene oxide in methanol as detailedin scheme 19 to furnish the title compound.

MS (ESPOS): 473.3 [M+H]⁺.

Example 89 4-Butyl-4-fluoro-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

The synthesis of boc-protected4-Fluoro-4-butyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester,12d (P=Boc, m=2, R⁹=n-butyl) from the starting material(2S)-4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester usesgeneral method Q, depicted in scheme 12 utilizing 1-butyne anion as afour carbon synthon in the 4-ketone alkylation step. Preparation of thestarting material, 4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butylester is described by Bousquet, Y.; Anderson, P. C.; Bogri, T.; DuceppeJ.; Grenier, L.; Guse, I.; Tetrahedron, 1997, 53 15671-15680.

Lincosamide 6b (R²=H, R³=Cl) was coupled to 12d (P=Boc, m=2, R⁹=butyl)to provide intermediate 13a (R²=H, R³=Cl, R⁹=butyl, P¹=H, P²=Boc, m=2)which was deprotected under acidic conditions to provide the titlecompound as depicted in general method Z.

MS (ESPOS): 457.0 [M+H]⁺.

Example 90 4-Cyclopropylmethyl-4-fluoro-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamide 6b (R²=H, R³=Cl) was coupled to 12d (P=Boc, m=2,R⁹=cyclopropylmethyl) to provide intermediate 13a (R²=H, R³=Cl,R⁹=cyclopropylmethyl, P¹=H, P²=Boc, m=2) which was deprotected underacidic conditions to provide the title compound as depicted in generalmethod Z.

MS (ESPOS): 455.0 [M+H]⁺.

Example 91 3-Butyl-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

To a solution of azetedine acid 25f (R⁹=butyl) (52 mg, 0.20 mmol, 1equiv), 7-Cl MTL 6b (R²=H, R³=Cl) (58 mg, 0.20 mmol, 1 equiv) and HBTU(84 mg, 0.22 mmol, 1.1 equiv) in DMF (2.0 mL) at 23° C. was added DIPEA(88 μL, 0.51 mmol, 2.5 equiv). After stirring for 12 h at 23° C., DMFwas removed in vacuo then the residue was partitioned between EtOAc (100mL) and 1:1 brine: 10% aqueous citric acid (100 mL). The organic layerwas separated and washed with 1:1 brine/saturated aqueous NaHCO₃ (100mL), brine (50 mL), dried (MgSO₄), filtered and concentrated to furnish82 mg (0.17 mmol, 84%) 13a (R²=H, R³=Cl, R⁹=butyl, P¹=H, P²=carboxylicacid-t-butyl ester, m=0) as a glassy solid which was used withoutpurification in the next step.

To a solution of carbamate 13a (R²=H, R³=Cl, R⁹=butyl, P¹=H, P²=Boc,m=0) (82 mg, 0.17 mmol, 1equiv) in 1,2-dichloroethane (10 mL) at 23° C.was added H₂O (0.40 mL) followed by TFA (4.0 mL). After stirring for 20min at 23° C., toluene (50 mL) was added and the resulting solution wasconcentrated to dryness. The residue was purified by semi-preparativeHPLC (Waters Nova-Pak® HR C₁₈, 6 μm particle size, 60 Å pore size, 20 mmID×100 mm, 5-60% acetonitrile in H₂O w/0.1% HCl over 30 min, 20 mL/minflow rate) to give 41 mg of title compound as a white solid.

¹H NMR (300 MHz, CD₃OD) δ 5.30 (d, J=6.0 Hz, 1 H), 4.64 (d, J=7.8 Hz, 1H), 4.63-4.52 (m, 2 H), 4.29 (d, J=10.2 Hz, 1 H), 4.07 (dd, J=5.7, 10.2Hz, 1 H), 4.00 (t, J=6.6 Hz, 1 H), 3.82 (d, J=3.3 Hz, 1 H), 3.75 (dd,J=8.4, 9.9 Hz, 1 H), 3.56 (dd, J=3.3, 10.2 Hz, 1 H), 2.92-2.76 (m, 1 H),2.14 (s, 3 H), 1.90-1.67 (m, 2 H), 1.45 (d, J=6.6 Hz, 3 H), 1.44-1.24(m, 4 H), 0.93 (t, J=6.9 Hz, 3 H); MS (ESPOS): 411.0 [M+H]⁺.

Example 92 3-Cyclopropylmethyl-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamine 6b (R²=H, R³=Cl) was coupled to azetedine acid 25f(R⁹=cyclopropylmethyl) as in general method Z to provide intermediate13a (R²=H, R³=Cl, R⁹=cyclopropylmethyl, P¹=H, P²=Boc, m=0) which wasdeprotected under acidic conditions to provide the title compound.

¹H NMR (300 MHz, CD₃OD) δ 5.30 (d, J=5.7 Hz, 1 H), 4.70 (d, J=7.5 Hz, 1H), 4.63-4.54 (m, 2 H), 4.29 (d, J=9.9 Hz, 1 H), 4.08 (dd, J=5.7, 10.2Hz, 1 H), 4.02 (t, J=9.3 Hz, 1 H), 3.88-3.80 (m, 2 H), 3.57 (dd, J=3.3,10.2 Hz, 1 H), 3.05-2.91 (m, 1 H), 2.14 (s, 3 H), 1.90-1.65 (m, 1 H),1.57-1.46 (m, 1 H), 1.47 (d, J=6.6 Hz, 3 H), 0.80-0.64 (m, 1 H),0.58-0.47 (m, 2 H), 0.16-0.10 (m, 2 H); MS (ESPOS): 409.2 [M+H]⁺.

Example 93 3-Propyl-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamine 6b (R²H, R³=Cl) was coupled to azetedine acid 25f(R⁹=propyl) as in general method Z to provide intermediate 13a (R²=H,R³=Cl, R⁹=propyl, P¹=H, P²=Boc, m=0) which was deprotected under acidicconditions to provide the title compound.

¹H NMR (300 MHz, CD₃OD) δ 5.31 (d, J=5.7 Hz, 1 H), 4.66 (d, J=7.5 Hz, 1H), 4.63-4.54 (m, 2 H), 4.31 (d, J=9.9 Hz, 1 H), 4.09 (dd, J=5.4, 10.2Hz, 1 H), 4.03 (t, J=9.6 Hz, 1 H), 3.83-3.74 (m, 2 H), 3.57 (dd, J=3.3,10.2 Hz, 1 H), 2.95-2.80 (m, 1 H), 2.15 (s, 3 H), 1.88-1.66 (m, 2 H),1.47 (d, J=6.9 Hz, 3 H), 1.46-1.30 (m, 2 H), 0.97 (t, J=7.2 Hz, 3 H); MS(ESPOS): 397.0 [M+H]⁺.

Example 94 3-Butyl-1-(2-hydroxy-ethyl)-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

A sample of 3-Butyl-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amideprepared in example 91 was alkylated with ethyleneoxide as depicted inscheme 19 (R⁶=2-hydroxyethyl) to provide the title compound.

¹H NMR (300 MHz, CD₃OD) δ 5.30 (d, J=5.4 Hz, 1 H), 4.67-4.57 (m, 1 H),4.46-4.37 (m, 1 H), 4.29-4.24 (m, 1 H), 4.13-4.06 (m, 1 H), 3.83-3.78(m, 1 H), 3.67-3.55 (m, 3 H), 3.44-3.32 (m, 1 H), 2.75-2.57 (m, 2 H),2.44-2.34 (m, 1 H), 2.14 (s, 3 H), 1.80-1.40 (m, 6 H), 1.39-1.20 (m, 5H), 0.95-0.86 (m, 3 H); MS (ESPOS): 455.0 [M+H]⁺.

Example 95 3-Butyl-1-methyl-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

To a solution of Boc-carbamate 25f (R⁹=butyl) (236 mg, 0.92 mmol, 1equiv) in aqueous formaldehyde (37%, 2.0 mL) at 23° C. was added formicacid (95%, 1.0 mL). The resulting mixture was heated at reflux for 4 h,then cooled to 23° C.; treated with t-BuOH (5.0 mL) and concentrated.The crude residue was dissolved/suspended in H₂O (15 mL), frozen andlyophilized. The resulting solid was dissolved in 1.0 N HCl (15 mL),filtered and concentrated. The resulting material wasdissolved/suspended in H₂O to yield a cloudy suspension that wasfiltered through a nylon membrane (0.2 μm) and concentrated to give 186mg of white solid, of which the major component is the desired3-butyl-1-methyl-azetidine-2-carboxylic acid hydrochloride salt. Thismaterial was used without further purification.

MS (ESPOS): 172.3 [M+H].

Lincosamine 6b (R²=H, R³=Cl) was coupled to3-butyl-1-methyl-azetidine-2-carboxylic acid hydrochloride salt as ingeneral method Z to provide the title compound.

¹H NMR (300 MHz, D₂O) δ 5.40 (d, J=5.7 Hz, 1 H), 4.73 (d, J=7.8 Hz, 1H), 4.66-4.56 (m, 1 H), 4.48 (dd, J=1.2, 9.9 Hz, 1 H), 4.38-4.27 (m, 2H), 4.11 (dd, J=5.7, 10.5 Hz, 1 H), 3.88 (d, J=3.0 Hz, 1 H), 3.81 (t,J=9.6 Hz, 1 H), 3.67 (dd, J=3.3, 10.5 Hz, 1 H), 3.04-2.87 (m, 1 H), 2.94(s, 3 H), 2.18 (s, 3 H), 1.90-1.68 (m, 2 H), 1.44 (d, J=6.9 Hz, 3 H),1.40-1.22. (m, 4 H), 0.87 (t, J=6.9 Hz, 3 H); MS (ESPOS): 425.3 [M+H]⁺.

Example 96 3-Pentyl-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamine 6b (R²=H, R³=Cl) was coupled to azetedine acid 25f(R⁹=pentyl) as in general method Z to provide intermediate 13a (R²=H,R³=Cl, R⁹=pentyl, P¹=H, P²=carboxylic acid-t-butyl ester, m=0) which wasdeprotected under acidic conditions to provide the title compound.

H NMR (300 MHz, CD₃OD) δ 5.30 (d, J=5.4 Hz, 1 H), 4.63-4.53 (m, 3 H),4.30 (d, J=9.6 Hz, 1 H), 4.08 (dd, J=5.7, 10.2 Hz, 1 H), 4.00 (t, J=9.6Hz, 1 H), 3.81 (d, J=2.4 Hz, 1 H), 3.74 (dd, J=7.8, 9.9 Hz, 1 H), 3.57(dd, J=3.3, 10.2 Hz, 1 H), 2.92-2.78 (m, 1 H), 2.15 (s, 3 H), 1.90-1.67(m, 2 H), 1.46 (d, J=6.9 Hz, 3 H), 1.44-1.26 (m, 6 H), 0.92 (t, J=7.5Hz, 3 H); MS (ESPOS): 425.0 [M+H]⁺.

Example 97 3-(3-Methyl-butyl)-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamine 6b (R²=H, R³=Cl) was coupled to azetedine acid 25f(R⁹=3-methyl-butyl) as in general method Z to provide intermediate 13a(R²=H, R³=Cl, R⁹=3-methyl-butyl, P¹=H, P²=carboxylic acid-t-butyl ester,m=0) which was deprotected under acidic conditions to provide the titlecompound.

¹H NMR (300 MHz, CD₃OD) δ 5.31 (d, J=5.4 Hz, 1 H), 4.63-4.53 (m, 2 H),4.30 (d, J=10.5 Hz, 1 H), 4.08 (dd, J=5.7, 10.5 Hz, 1 H), 4.00 (t, J=9.6Hz, 1 H), 3.81 (d, J=2.4 Hz, 1 H), 3.74 (dd, J=8.1, 9.9 Hz, 1 H), 3.57(dd, J=3.3, 10.2 Hz, 1 H), 2.88-2.75 (m, 1 H), 2.15 (s, 3 H), 1.90-1.67(m, 2 H), 1.63-1.50 (m, 1 H), 1.46 (d, J=6.9 Hz, 3 H), 1.39-1.10 (m, 3H), 0.94 (d, J=1.5 Hz, 3 H), 0.92 (d, J=1.5 Hz, 3 H); MS (ESPOS): 425.0[M+H]⁺.

Example 98 3-(3-Cyclopropyl-propyl)-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamine 6b (R²=H, R³=Cl) was coupled to azetedine acid 26f(R⁹=3-cyclopropyl-propyl) as in general method Z to provide intermediate13a (R²=H, R³=Cl, R⁹=butyl, P¹=H, P²=carboxylic acid-t-butyl ester, m=0)which was deprotected under acidic conditions to provide the titlecompound.

¹H NMR (300 MHz, CD₃OD) δ 5.29 (d, J=5.7 Hz, 1 H), 4.64-4.51 (m, 3 H),4.29 (d, J=10.2 Hz, 1 H), 4.07 (dd, J=5.7, 10.2 Hz, 1 H), 3.99 (t, J=9.9Hz, 1 H), 3.79 (d, J=3.3 Hz, 1 H), 3.74 (dd, J=8.4, 9.9 Hz, 1 H), 3.55(dd, J=3.3, 10.2 Hz, 1 H), 2.91-2.77 (m, 1 H), 2.13 (s, 3 H), 1.93-1.68(m, 2 H), 1.60-1.32 (m, 2 H), 1.44 (d, J=6.9 Hz, 3 H), 1.24 (q, J=10.2Hz, 2 H), 0.74-0.62 (m, 1 H), 0.44-0.36 (m, 2 H), 0.04-0.02 (m, 2 H); MS(ESPOS): 437.2 [M+H]⁺.

Example 99 3-(3-Cyclobutyl-propyl)-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamine 6b (R²=H, R³=Cl) was coupled to azetedine acid 26f(R⁹=3-cyclobutyl-propyl) as in general method Z to provide intermediate13a (R²=H, R³=Cl, R⁹=(3-cyclobutyl-propyl), P¹=H, P²=carboxylicacid-t-butyl ester, m=0) which was deprotected under acidic conditionsto provide the title compound.

¹H NMR (300 MHz, CD30D) δ 5.29 (d, J=5.7 Hz, 1 H), 4.63-4.46 (m, 3 H),4.28 (d, J=10.2 Hz, 1 H), 4.08 (dd, J=5.4, 10.2 Hz, 1 H), 3.89 (t, J=9.0Hz, 1 H), 3.79 (d, J=3.6 Hz, 1 H), 3.65 (dd, J=8.1, 9.6 Hz, 1 H), 3.56(dd, J=3.0, 10.2 Hz, 1 H), 2.86-2.71 (m, 1 H), 2.38-2.20 (m, 1 H), 2.14(s, 3 H), 2.10-1.96 (m, 2 H), 1.90-1.52 (m, 6 H), 1.44 (d, J=6.9 Hz, 3H), 1.44-1.14 (m, 4 H). MS (ESPOS): 451.2 [M+H]

Example 100 3-(2-Cyclobutyl-ethyl)-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamine 6b (R²=H, R³=Cl) was coupled to azetedine acid 26f(R⁹=2-cyclobutyl-ethyl) as in general method Z to provide intermediate13a (R²=H, R³=Cl, R⁹=2-cyclobutyl-ethyl, P¹=H, P²=carboxylicacid-t-butyl ester, m=0) which was deprotected under acidic conditionsto provide the title compound.

¹H NMR (300 MHz, CD₃OD) δ 5.29 (d, J=5.7 Hz, 1 H), 4.63-4.50 (m, 3 H),4.29 (d, J=10.2 Hz, 1 H), 4.08 (dd, J=5.4, 10.2 Hz, 1 H), 3.95 (t, J=9.3Hz, 1 H), 3.79 (d, J=3.0 Hz, 1 H), 3.69 (dd, J=8.4, 9.9 Hz, 1 H), 3.56(dd, J=3.3, 10.2 Hz, 1 H), 2.87-2.72 (m, 1 H), 2.38-2.20 (m, 1 H), 2.14(s, 3 H), 2.13-2.00 (m, 2 H), 1.94-1.55 (m, 6 H), 1.54-1.34 (m, 2 H),1.45 (d, J=6.6 Hz, 3 H); MS (ESPOS): 437.2 [M+H]⁺.

Example 101 3-(2-Cyclopropyl-ethyl)-azetidine2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamine 6b (R²=H, R³=Cl) was coupled to azetedine acid 26f(R⁹=2-cyclopropyl-ethyl) as in general method Z to provide intermediate13a (R²=H, R³=Cl, R⁹=2-cyclopropyl-ethyl, P¹=H, P²=carboxylicacid-t-butyl ester, m=0) which was deprotected under acidic conditionsto provide the title compound.

¹H NMR (300 MHz, CD₃OD) δ 5.29 (d, J=5.7 Hz, 1 H), 4.62-4.50 (m, 3 H),4.29 (d, J=10.2 Hz, 1 H), 4.07 (dd, J=5.4, 10.2 Hz, 1 H), 3.99 (t, J=9.6Hz, 1 H), 3.82-3.71 (m, 2 H), 3.56 (dd, J=3.3, 10.2 Hz, 1 H), 2.95-2.80(m, 1 H), 2.13 (s, 3 H), 2.00-1.77 (m, 2 H), 1.44 (d, J=6.9 Hz, 3 H),1.35-1.20 (m, 2 H), 0.74-0.62 (m, 1 H), 0.48-0.40 (m, 2 H), 0.09-0.02(m, 2 H); MS (ESPOS): 423.2 [M+H]⁺.

Example 102 3-(3,3-Difluoropropyl)-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Lincosamine 6b (R²=H, R³=Cl) was coupled to azetedine acid 26f(R⁹=3,3-difluoropropyl) as in general method Z to provide intermediate13a (R²=H, R³=Cl, R⁹=2-cyclopropyl-ethyl, P¹=H, P²=carboxylicacid-t-butyl ester, m=0) which was deprotected under acidic conditionsto provide the title compound.

¹H NMR (300 MHz, CD₃OD) δ 5.93 (t, J=57 Hz, 1 H), 5.29 (d, J=5.7 Hz, 1H), 4.64 (d, J=7.5 Hz, 1 H), 4.60-4.51 (m, 2 H), 4.29 (d, J=10.2 Hz, 1H), 4.07 (dd, J=5.7, 10.2 Hz, 1 H), 4.02 (t, J=8.7 Hz, 1 H), 3.82-3.74(m, 2 H), 3.55 (dd, J=3.3, 10.5 Hz, 1 H), 2.96-2.82 (m, 1 H), 2.13 (s, 3H), 2.06-1.76 (m, 4 H), 1.44 (d, J=6.9 Hz, 3 H); MS (ESPOS): 433.0[M+H]⁺.

Example 103 4-Pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide

2-Methyl-1-(3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidine-1-carboxylicacid tert-butyl ester. To a solution of2-(1-Amino-2-methyl-propyl)-6-propyl-tetrahydro-pyran-3,4,5-triolprepared by general method AB (51.9 mg, 0.21 mmol, 1 equiv) in dry DMF(4.5 mL) at 0° C. was added triethylamine (117 μL, 0.84 mmol, 4 equiv),followed by the addition of BSTFA (84 μL, 0.32 mmol, 1.5 equiv). Thereaction mixture was stirred at 0° C. for 10 minutes, and then wasstirred at RT for 45 minutes. To the reaction mixture was added theprotected amino acid 7d as prepared in general method L (R⁹=n-pentyl,P=Boc) (72 mg, 0.25 mmol, 1.2 equiv) and HATU (120 mg, 0.32 mmol, 1.5equiv). The reaction mixture was stirred at RT for 2 h, evaporated todryness, taken up in Et₂O (150 mL), washed with 10% citric acid (1×),saturated NaHCO₃ (1×) and brine. The organic layer was dried over MgSO₄and concentrated to give the crude product (190 mg) as a yellow oil. Theresidue was taken up DCE (6 mL), trifluoroacetic acid (4 mL) containingwater (0.2 mL) was added with stirring. The reaction mixture was stirredat RT for 1 h, then solvent was removed under vacuum by repeatedco-evaporation from DCE. The residue was purified by columnchromatography on silica 10% 0.25M NH₃ in MeOH/DCM to give the product(38.4 mg, 43%).

¹H NMR (300 MHz, D₂O) δ 4.37 (dd, J=4.7, 9.1, 1), 4.14 (dd, J=3.0, 9.6,1), 3.97-3.90 (m, 2), 3.70 (d, J=2.8, 1), 3.62-3.51 (m, 3), 2.89 (dd,J=9.1, 11.3, 1), 2.33-2.03 (m, 1), 1.64-1.55 (m, 2), 1.52-1.45 (m, 3),1.36-1.25 (m, 6), 1.0-0.86 (m,. 12); MS (ESPOS): 416.6 [M+H].

Example 104 4-Propyl-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound in example 2 was prepared according to the processdescribed in example 103 using intermediate 10b, prepared in generalmethod O (R⁹=n-propyl).

(ESPOS): 401.7 [M+H]⁺.

Example 105 4-Propyl-piperidine-2-carboxylic acid{2-methyl-1-[3,4,5-trihydroxy-6-(2,2,2-trifluoro-ethylsulfanyl)-tetrahydro-pyran-2-yl]-propyl}-amide

Intermediate 27a prepared in general method *4-propyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester.

MS (ESNEG): 270.2 [M−H]⁻.

The title compound was prepared according to the processes described ingeneral method R and illustrated in Scheme 16, 1,1,1trifluoroethanethiol was used as the thiol nucleophille. Coupling theprotected amino acid intermediate 4-Propyl-piperidine-1,2-dicarboxylicacid 1-tert-butyl ester and deprotection were conducted as in example103.

(ESPOS): 473.7 [M+H]⁺.

Example 106 4-Pentyl-pyrrolidine-2-carboxylic acid[1-(6-ethoxyethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide

2-[1-(6-Allyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-yl)-2-methyl-propylcarbamoyl]-4-pentyl-pyrrolidine-1-carboxylicacid tert-butyl ester. To a stirred solution of building block 15c (650mg, 1.26 mmol, 1 equiv) and protected amino acid 7d (R⁹=pentyl, P=Boc)(395 mg, 1.39 mmol, 1.1 equiv) in dry DMF (5.0 mL) at 0° C. was addedDIEA (0.88 mL, 5.0 mmol, 4 equiv), followed by the addition of solidHATU (956 mg, 2.52 mmol, 2.0 equiv). The reaction mixture was stirred atRT for 3 h, evaporated to dryness, taken up in ethyl acetate, washedwith 10% citric acid (1×), water (1×), saturated NaHCO₃ (1×) and brine.The organic layer was dried over Na₂SO₄ and concentrated. to give ayellow syrup. The filtrate was concentrated and the residue was purifiedby column chromatography on silica 10% EtOAc/Hexanes to 20%EtOAc/Hexanes to give the product2-[1-(6-Allyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-yl)-2-methyl-propylcarbainoyl]-4-pentyl-pyrrolidine-1-carboxylicacid tert-butyl ester a colorless oil (897 mg, 89%).

2-{2-Methyl-1-[3,4,5-tris-benzyloxy-6-(2-hydroxy-ethyl)-tetrahydro-pyran-2-yl]-propylcarbamoyl}-4-pentyl-pyrrolidine-1-carboxylicacid tert-butyl ester. A stirred solution of (634 mg, 0.81 mmol, 1equiv) in DCM (60 mL) at −78° C. was treated with a stream of ozone inoxygen for 20 min a persistant pale blue color was observed. After 30min excess ozone was removed with a stream of N₂ and a solution of DMS(3 mL) in DCM (10 mL) was added, the solution allowed to warm to RTovernight. The solution was evaporated to driness and the residuedissolved in EtOH (50 mL) cooled to 0° C. and treated with NaBH₄ (300 mg8.1 mmol, 10 equiv) after 1 h excess NaBH₄ was destroyed by acidifyingthe reaction mixture the solvent was removed and the crude productpurified by column chromatography on silica 20% EtOAc/Hexanes to givethe alcohol product (304 mg, 47%).

2-{2-Methyl-1-[3,4,5-tris-benzyloxy-6-(2-ethoxy-ethyl)-tetrahydro-pyran-2-yl]-propylcarbamoyl}-4-pentyl-pyrrolidine-1-carboxylicacid tert-butyl ester. To a stirred solution of washed NaH (4.4 mg 0.183mmol, 1 equiv) in THF (0.8 mL) at 0° C. was added alcohol intermediate2-{2-Methyl-1-[3,4,5-tris-benzyloxy-6-(2-hydroxy-ethyl)-tetrahydro-pyran-2-yl]-propylcarbamoyl}-4-pentyl-pyrrolidine-1-carboxylicacid tert-butyl ester (144 mg, 0.183 mmol, 1 equiv) after 10 min EtI (73μL, 0.92 mmol, 5.0 equiv) was added and the reaction mixture stirredovernight. The reaction mixture evaporated to dryness, The filtrate wasconcentrated and the residue was purified by preparative 30%EtOAc/Hexanes to give the product2-{2-Methyl-1-[3,4,5-tris-benzyloxy-6-(2-ethoxy-ethyl)-tetrahydro-pyran-2-yl]-propylcarbamoyl}-4-pentyl-pyrrolidine-1-carboxylicacid tert-butyl ester (33.8 mg 22%) a colorless oil.

4-Pentyl-pyrrolidine-2-carboxylic acid[1-(6-ethoxymethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide.2-{2-Methyl-1-[3,4,5-tris-benzyloxy-6-(2-ethoxy-ethyl)-tetrahydro-pyran-2-yl]-propylcarbamoyl}-4-pentyl-pyrrolidine-1-carboxylicacid tert-butyl ester (33.8 mg) and degussa 50% w/w wet 10%palladium/carbon (80 mg) suspended in MeOH (3 mL) was stirred 20 h under1 atm pressure H₂. The reaction mixture was filtered through Celiteevaporated to driness to provide the crude product which was purified bycolumn chromatography on silica 3% to 5% MeOH/DCM to give the bocprotected ether product (19 mg) which was taken up in DCE (1 mL),trifluoroacetic acid (1 mL) containing water (0.05 mL) was added withstirring. The reaction mixture was stirred at RT for 1 h, then solventwas removed under vacuum by repeated co-evaporation from DCE.Lyophylization of the TFA salt from 1:1 MeCN/water containing excessdilute HCl gave the title compound (13.0 mg 66%).

¹H NMR (300 MHz, D₂O) δ 4.47-4.38 (m, 1), 4.21-4.16 (m, 1), 4.11-4.06(m, 1), 3.96 (dd, J=6.3, 9.6, 1), 3.81 (s, 1), 3.61-3.50 (m, 7), 2.92(dd, J=9.9, 9.9, 1), 2.33-1.98 (m, 7), 1.96-1.82 (m, 1), 1.47-1.33 (m,11), 1.18 (t, J=6.9, 3), 0.97-0.89 (m, 12); MS (ESPOS): 446.4 [M+H].

Example 107 1-(2-Hydroxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide

The title compound was prepared according to the process illustrated inScheme 19. Ethylene oxide was used as the alkylating agent. To a stirredsolution of 4-Pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide(example 103) (12.0 mg 0.029 mmol, 1 equiv) and TEA (100 μL) in MeOH (2mL) at 0° C. was added condensed ethylene oxide (200 μL) was added andthe reaction mixture stirred 48 h. The reaction mixture evaporated todryness, and the resulting residue was purified by column chromatographyon silica 20% 0.25M NH₃ in MeOH/DCM to give the crude N alkylatedproduct. The crude product was taken up in Et₂O, filtered and thefiltrate treated with 2M HCl in Et₂O, the precipetated HCl salt wascollected washed with Et₂O and lyophylized to give the title compound asa colorless powder (4.4 mg 34%).

MS (ESPOS): 473.6 [M+H]⁺.

Example 108 4-Pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-propyl]-amide

2-{2-Methyl-1-[3,4,5-tris-hydroxy-tetrahydro-pyran-2-yl]-propylcarbamoyl}-4-pentyl-pyrrolidine-1-carboxylicacid tert-butyl ester. To a stirred solution of damp Raney nickel R1(300 mg) suspended in EtOH (5 mL) under N₂ was added a solution of1-(2-(S)-4-(R)-n-pentylpyrrolidin-2-yl)-N-{1-(R)-[2-(S)-3-(S), 4-(S),5-(R)-trihydroxy-6-(R)-(methylthio)tetrahydropyran-2-yl]-2-methylprop-1-yl}acetamide.(85.0 mg 0.164 mmol, 1 equiv) in EtOH (5 mL). The reaction mixture wasrefluxed 2 h cooled to RT, filtered through Celite and evaporated todriness to provide the crude product (66 mg) which was purified bycolumn chromatography on silica 3% MeOH/DCM to give the N-Boc protecteddes-thiomethyl product (42.7 mg 55%).

TLC R_(f)=0.27 (10% MeOH/DCM); MS (ESPOS): 473.6 [M+H]⁺, (ESNEG): 507.5[M+HCl].

4-Pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-propyl]-amide.N-Boc protected product des-thiomethyl product was taken up DCE (5 mL),trifluoroacetic acid (5 mL) containing water (0.1 mL) was added withstirring. The reaction mixture was stirred at RT for 40 min, thensolvent was removed under vacuum by repeated co-evaporation from DCE.The residue was dissolved in 1:1 MeCN/water cooled to 0° C. and 1M HCl(0.5 mL) was added, the solution was filtered and lyophylized to givethe title compound (26 mg, 43%) as a colorless powder.

TLC (CHCl₃:MeOH:32% aq. AcOH) R_(f)=0.58; MS (ESPOS) 387.3 [M+H]⁺.

Examples 109-127, 142, and 143 may be made according to the methodsdescribed herein.

Example 109 4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Example 110 5-Propyl-azepane-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Example 111 5-Propyl-azepane-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-isopropylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Example 112 5-Propyl-azepane-2-carboxylic acid[1-(6-tert-butylsulfanyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide

Example 113 5-Propyl-azepane-2-carboxylic acid[(4-chloro-phenyl)-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-methyl]-amide

Example 114 4-Pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide

Example 115 4-Pentyl-pyrrolidine-2-carboxylic acid[1-(6-butoxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amideExample 116 4-Butyl-1-methyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide

Example 117 Phosphoric acidmono-(4,5-dihydroxy-6-{2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl)-amino]-propyl}2-propyl-tetrahydro-pyran-3-yl)ester

Example 118 Hexadecanoic acid4,5-dihydroxy-6-{2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl)-amino]-propyl}-2-propyl-tetrahydro-pyran-3-ylester

Example 119 Phosphoric acidmono-(4,5-dihydroxy-6-{2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl)-amino]-propyl}2-propyl-tetrahydro-pyran-3-yl)ester

Example 120 Hexadecanoic acid4,5-dihydroxy-6-{2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl)-amino]-propyl}-2-propyl-tetrahydro-pyran-3-ylester

Example 1211-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide

Example 1222-[2-Methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propylcarbamoy]-4-pentyl-pyrrolidine-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

Example 1231-(5-Methyl-2-oxo-[1,3]dioxol4-ylmethyl)-4-propyl-pyrrolidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide

Example 1242-[2-Methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-pyrrolidine-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

Example 125 4-Propyl-pyrrolidine-2-carboxylic acid{2-methyl-1-[3,4,5-trihydroxy-6-(2-hydroxy-ethyl)-tetrahydro-pyran-2-yl]-propyl}-amide

Example 126 4-Propyl-pyrrolidine-2-carboxylic acid{2-methyl-1-[3,4,5-trihydroxy-6-(3-hydroxy-propyl)-tetrahydro-pyran-2-yl]-propyl}-amide

Example 127 4-Propyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-propyl]-amide

Example 142 4-Propyl-pyrrolidine-2-carboxylic acid{2-methyl-1-[3,4,5-trihydroxy-6-(2-methylsulfanyl-ethyl)-tetrahydro-pyran-2-yl]-propyl}-amide

Example 143 4-Propyl-pyrrolidine-2-carboxylic acid[1-(6-cyclopropylmethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide

Specific prodrug examples 128-141 below are prepared from the respectiveparent compounds (see above) using methods as described hereinabove.

Example 128 Phosphoric acidmono-(6-{2-chloro-1-[(5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl)ester

Example 129 Hexadecanoic acid6-{2-chloro-1-[(5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-ylester

Example 130 Phosphoric acidmono-(6-{2-chloro-1-[(5-fluoro-5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl)ester

Example 131 Hexadecanoic acid6-{2-chloro-1-[(5-fluoro-5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-ylester

Example 1322-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-fluoro-5-propyl-azepane-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

Example 1335-Fluoro-1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-5-propyl-azepane-2-carboxylicacid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Example 1345-Cyclopropylmethyl-1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-azepane-2-carboxylicacid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Example 1352-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-cyclopropylmethyl-azepane-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

Example 136 Hexadecanoic acid6-{2-chloro-1-[(5-cyclopropylmethyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-ylester

Example 137 Phosphoric acidmono-(6-{2-chloro-1-[(5-cyclopropylmethyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl)ester

Example 138 Hexadecanoic acid6-{2-chloro-1-[(4-fluoro-4-propyl-piperidine-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-ylester

Example 139 Phosphoric acidmono-(6-{2-chloro-1-[(4-fluoro-4-propyl-piperidine-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl)ester

Example 1402-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-fluoro-4-propyl-piperidine-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

Example 1414-Fluoro-1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylicacid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide

Example A Susceptibility Testing

Compounds were tested following the microdilution method of NCCLS(National Committee for Clinical Laboratory Standards. Methods fordilution antimicrobial susceptibility tests for bacteria that growaerobically; Approved standard—fifth edition. NCCLS document M7-A5,NCCLS, Wayne, Pa. 2000; National Committee for Clinical LaboratoryStandards. Methods for antimicrobial susceptibility testing of anaerobicbacteria; Approved standard—fifth edition. NCCLS document M11-A4, NCCLS,Wayne, Pa. 2001). Assays were performed in sterile plastic 96-wellmicrotiter trays with round bottom wells (Greiner).

Compound Preparation

Stock solutions of test compounds and control antibiotics are preparedat 10 mg/ml in DMSO. Serial 2-fold dilutions of each drug are performedin a microtiter plate across each row using DMSO as solvent at 100-foldthe desired final concentration. Wells in columns #1-11 contain drug andcolumn #12 was kept as a growth control for the organism with no drug.Each well in the mother plate is diluted with sterile deionized water,mixed, and volumes of 10 μl distributed to each well in the resultingassay plates.

Preparation of Inoculum

Stock cultures were prepared using the Microbank™ method (Pro-LabDiagnostics) and stored at −80° C. To propagate aerobic strains, onebead was removed from the frozen vial and aseptically streaked ontoTrypticase Soy Agar (Difco), Chocolate Agar (Remel) or Blood Agar(Remel), which were incubated at 35° C. overnight. Anaerobes werecultivated in Brucella Agar (Remel) supplemented with hemin and vitaminK and incubated in anaerobiosis using an Anaerobic Jar (Mitsubishi) at35° C. for 24 to 48 h. Standardized inocula were prepared using thedirect colony suspension method according to NCCLS guidelines (NationalCommittee for Clinical Laboratory Standards. Methods for dilutionantimicrobial susceptibility tests for bacteria that grow aerobically;Approved standard—fifth edition. NCCLS document M7-A5, NCCLS, Wayne, Pa.2000; National Committee for Clinical Laboratory Standards. Methods forantimicrobial susceptibility testing of anaerobic bacteria; Approvedstandard—fifth edition. NCCLS document M11-A4, NCCLS, Wayne, Pa. 2001).Isolated colonies were selected from an 18-24 hr agar plate andresuspended in 0.9% sterile saline to match a 0.5 McFarland turbiditystandard. The suspension was used within 15 minutes of preparation.Streptococcus pneumoniae VSPN1001 Streptococcus pneumoniae ATCC 49619Streptococcus pneumoniae VSPN3026 Streptococcus pneumoniae R6xStreptococcus pneumoniae VSPN4054 Streptococcus pneumoniae 488KStreptococcus pneumoniae VSPN4021 Streptococcus pneumoniae 9Staphylococcus aureus VSAU1017 Staphylococcus aureus SmithStaphylococcus aureus VSAU1003 Staphylococcus aureus ATCC 25923Staphylococcus aureus VSAU4020 Staphylococcus aureus 125 Staphylococcusaureus VSAU4048 Staphylococcus aureus 85-EPI Staphylococcus aureusVSAU4065 Staphylococcus aureus VSAU4065 Staphylococcus epidermidisVSEP1001 Staphylococcus epidermidis ATCC 12228 Enterococcus faecalisVEFL1003 Enterococcus faecalis ATCC 51299 Enterococcus faecium VEFA1005Enterococcus faecium BM4147.1 Haemophilus influenzae VHIN1003Haemophilus influenzae ATCC 49766 Haemophilus influenzae VHIN1004Haemophilus influenzae ATCC 31517 Haemophilus influenzae VHIN1005 acrHaemophilus influenzae LS-2 Moraxella catarrhalis VMCA1001 Moraxellacatarrhalis ATCC 25238 Escherichia coli VECO2096 Escherichia coli MG1655Escherichia coli VECO2526 tolC Escherichia coli MG1655 tolC Bacteroidesfragilis VBFR1001 Bacteroides fragilis ATCC 25285 Bacteroidesthetaiotaomicron VBTH Bacteroides thetaiotaomicron 1001 ATCC #29741Clostridium difficile VCDI1001 Clostridium difficile ATCC 9689Preparation of Assay Plates for MICs Preparation of Assay Plates forMICs

Media were prepared at 1.1× concentration. Mueller-Hinton Broth MHB(Difco) supplemented with Ca++ and Mg++ as recommended by NCCLS, MHBsupplemented with 5% horse lysed blood, HTM Broth (Remel), or Brucellabroth (Remel) supplemented with hemin and vitamin K. For each organism,the standardized suspension was diluted into appropriate growth mediumin a sterile reservoir. After mixing, wells in the drug-containing assayplates were inoculated with a volume of 90 μl. Thus, for each MICdetermination, each well contains a final volume of 100 μl with aninoculum size of approximately 5*105 cfu/ml and no more than 1% DMSO.

Interpretation of MIC

The completed microtiter plates were incubated 16-20 h at 35° C. inambient air for aerobes, and at 35° C. for 46-48 h or in an anaerobe jar(Mitsubishi) for anaerobes. Optical density of each well was determinedat 600 nm using a VersaMax Microplate reader (Molecular Devices,Sunnyvale, Calif.). The MIC was defined as the lowest drug concentrationcausing complete suppression of visible bacterial growth.

Example 47 isomer I and Example 47 isomer II possessed in vitro potencyagainst the Gram negative organism Haemophilus influenzae with an MIC≦4μg/mL. Examples 47 isomers 1 and 2 further displayed an MIC of 0.5 μg/mLagainst H. influenzae strain ATCC 31517, compared with clindamycin,which displayed an MIC of 8 μg/mL against H. influenzae strain ATCC31517.

Example B Efficacy in Murine S. aureus Septicemia

Efficacy studies were performed in an S. aureus murine septicemia modelaccording to models published elsewhere (Goldstein, B. P., G. Candiani,T. M. Arain, G. Romano, I. Ciciliato, M. Berti, M. Abbondi, R. Scotti,M. Mainini, F. Ripamonti, and et al. 1995. Antimicrobial activity of MDL63,246, a new semisynthetic glycopeptide antibiotic Antimicrob AgentsChemother. 39:1580-1588.; Misiek, M., T. A. Pursiano, F. Leitner, and K.E. Price 1973. Microbiological properties of a new cephalosporin, BL-S339:7-(phenylacetimidoyl-aminoacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)ceph-3-em-4-carboxylic acid Antimicrob Agents Chemother.3:40-48).

Compound Preparation

Compounds were dissolved in 2% Tween 80 for oral dosing or 0.9% NaClsolution for intravenous dosing. Compounds were administered at 1 hourafter bacterial inoculation. Vancomycin or ampicillin were used ascontrols.

Efficacy Model

Male or female ICR mice weighing 22±2 g from MDS Pharna Services wereused for the evaluation. Food and water was given ad libitum. Groups of6 mice weighing 22±g were used for the experiment. Mice were inoculatedintraperitoneally with Staphylococcus aureus Smith at 4 104 CFU in 0.5ml of Brain Heart Infusion Broth (Difco) containing 5% mucin (Sigma).Mortality was recorded once daily for 7 days following bacterialinoculation.

While the invention has been described and illustrated herein byreferences to various specific material, procedures and examples, it isunderstood that the invention is not restricted to the particularmaterial combinations of material, and procedures selected for thatpurpose. Numerous variations of such details can be implied as will beappreciated by those skilled in the art.

1. A compound of Formula (IA):

wherein: the

 represents a bond that may be a double bond or a single bond; R¹ isselected from the group consisting of —S-alkyl, —S-substituted alkyl,SMe, S-(2-hydroxyethyl), (heteroaryl)alkyl, hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy,cycloalkylalkyl, halo, and substituted alkylsulfanyl; R²and R³ areindependently hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substitutedalkylsulfanyl, hydroxy, halo, or one of R²¹and R³ is ═NOR⁷ and the otheris absent; R⁶ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, (carboxamido)alkyl, (carbamoyl)alkyl, alkoxycarbonyl,(alkoxycarbonyl)alkyl, (alkoxycarbonylamino)alkyl, or —N(R⁶)— fragmentis part of the amidine, N-cyanoamidine, N-hydroxyamidine, orN-alkoxyamidine structure; R⁷ is selected from the group consisting ofhydrogen and alkyl; R⁹, which can be singly or multiply substituted inthe ring on the same or different carbons, is independently selectedfrom the group consisting of hydrogen, substituted alkyl, halo,substitutedalkenyl, alkenyl, (heteroaryl)alkenyl, and —S(O)_(q)R¹³ whereq is an integer equal to zero, one or two and R¹³ is selected from thegroup consisting of alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic; and wherein m=0-2; and wherein t=0-3; or pharmaceuticallyacceptable salts and/or prodrugs thereof; with the proviso excluding thefollowing compounds: the compounds when

 is a single bond and each R⁹ is hydrogen; and the compounds when

 is a single bond, R⁹ is substituted alkyl having a single substituentsaid single substituent is other than halo, oxygen, hydroxy, primaryamine, amine(secondary alkyl substituted by alkyl above), amine(tertiary alkyl substituted by alkyl as above), sulfur, —SH, phenyl, or—(CH₂)_(n)NR′R″ where n is an integer of from 1 to 8 and R′ and R″ arehydrogen or alkyl; and the compounds when

 is a single bond, R⁹ is halo.
 2. A compound of Formula (IA):

the

 represents a bond that may be a double bond or a single bond; R¹ isselected from the group consisting of —S-alkyl, —S-substituted alkyl,SMe, S-(2-hydroxyethyl), (heteroaryl)alkyl, hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy,cycloalkylalkyl, halo, and substituted alkylsulfanyl; R²and R³ areindependently hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substitutedalkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷ and the otheris absent; R⁶ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, (carboxamido)alkyl, (carbamoyl)alkyl, alkoxycarbonyl,(alkoxycarbonyl)alkyl, (alkoxycarbonylamino)alkyl, or —N(R⁶)— fragmentis part of the amidine, N-cyanoamidine, N-hydroxyamidine, orN-alkoxyamidine structure; R⁷ is selected from the group consisting ofhydrogen and alkyl; R⁹, which can be singly or multiply substituted inthe ring on the same or different carbons, is independently selectedfrom the group consisting of hydrogen, substituted alkyl, halo,substitutedalkenyl, alkenyl, (heteroaryl)alkenyl, and —S(O)_(q)R¹³ whereq is an integer equal to zero, one or two and R¹³ is selected from thegroup consisting of alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic; and wherein m=0-2; and wherein t=0-3; or pharmaceuticallyacceptable salts and/or prodrugs thereof; with the proviso excluding thefollowing compounds: the compounds when

 is a single bond and each R⁹ is hydrogen; and the compounds when

 is a single bond, R⁹ is substituted alkyl having a single substituentsaid single substituent is other than halo, oxygen, hydroxy, primaryamine, amine(secondary alkyl substituted by alkyl above), amine(tertiary alkyl substituted by alkyl as above), sulfur, —SH, phenyl, or—(CH₂)_(n)NR′R″ where n is an integer of from 1 to 8 and R′ and R″ arehydrogen or alkyl; and the compounds when

 is a single bond, R⁹ is halo.
 3. The compound of either claim 1 or 2wherein wherein the nitrogen-containing ring in Formulas (I) and (II) isselected from:


4. A compound selected from the group consisting of:1-(2-(S)-4-(S)-(ethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S), 3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(R)-(ethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S), 3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(R)-(ethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S), 3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-chloro-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(ethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S), 3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-chloro-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(3-p-fluorophenyl)thiopyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S), 4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(n-butylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S), 3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(3,3,3-trifluoroprop-1-yl-thio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S), 4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(2-(2-chlorophenyl)-ethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S), 4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(3-methylbut-1-ylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S), 4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(2-ethoxythiol)-ethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S), 4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(2,2,2-trifluoroethylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S), 4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(m-methylphenyl)methylsulfanylpyrrolidin-2-yl)-N-{1-(R)-[2-(S),3-(S), 4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(p-pyridinylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S), 3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(p-trifluoromethoxyphenyl)methylsulfanyl)-N-{1-(R)-[2-(S),3-(S), 4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(o,p-dichlorophenyl)methylsulfanyl)-N-{1-(R)-[2-(S),3-(S), 4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;1-(2-(S)-4-(S)-(p-pyridinylthio)pyrrolidin-2-yl)-N-{1-(R)-[2-(S), 3-(S),4-(S),5-(R)-trihydroxy-6-(R)-(methylsulfanyl)tetrahydropyran-2-yl]-2-hydroxy-prop-1-yl}acetamide;4-(Thiophen-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(4-Fluoro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(4-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(Pyridin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(Pyrazin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Butylsulfanyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3,3-Difluoro-allyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Pyridin-4-yl-allyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Pyridin-4-yl-propyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Methoxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methlylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(1H-imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Formylamino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Amino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Cyclohexyloxy-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;{2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidin-1-yl}-aceticacid methyl ester;1-Methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[3-(Furan-2-ylmethylsulfanyl)-propyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[3-(Thiophen-2-ylsulfanyl)-propyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Methoxyimino-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[2-(4-Ethyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Ethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Ethoxyimino-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Pyrrol-1-ylmethyl-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid 9H-fluoren-9-ylmethyl ester;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid ethyl ester; 4-(3-Cyano-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid phenyl ester;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid phenyl ester;4-(2-[1,2,3]Triazol-1-yl-ethyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propylidene-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;and 4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,45-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(4-Fluoro-phenylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Butylsulfanyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3,3,3-Trifluoro-propylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2-Chloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Methyl-butylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[2-(2-Mercapto-ethoxy)-ethylsulfanyl]-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2,2,2-Trifluoro-ethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(Pyridin-4-ylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(4-Trifluoromethoxy-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(Thiophen-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(4-Fluoro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(4-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(Pyridin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(Pyrazin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Butylsulfanyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3,3-Difluoro-allyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Pyridin-4-yl-allyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Pyridin-4-yl-propyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Methoxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(1H-Imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Formylamino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Amino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Cyclohexyloxy-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;{2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidin-1-yl}-aceticacid methyl ester;1-Methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[3-(Furan-2-ylmethylsulfanyl)-propyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[3-(Thiophen-2-ylsulfanyl)-propyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-imidazol-1-yl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Methoxyimino-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[2-(4-Ethyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Ethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Ethoxyimino-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Pyrrol-1-ylmethyl-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid 9H-fluoren-9-ylmethyl ester;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid ethyl ester; 4-(3-Cyano-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid phenyl ester;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid phenyl ester;4-(2-[1,2,3]Triazol-1-yl-ethyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propylidene-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;and 4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.5. A compound of Formula (IB):

wherein: R¹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl; R² andR³are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl,substituted alkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷and the other is absent; R⁶ is H, alkyl, or hydroxyalkyl; R⁷ is H oralkyl; R⁹, which can be singly or multiply substituted in the ring onthe same or different carbons, is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,substituted oxygen, substituted nitrogen, halogen, phenyl, substitutedphenyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—NR⁴R⁵, and branched chain isomersthereof wherein n is an integer of from 1 to 8 inclusive and R⁴ and R⁵are H or alkyl; and m is 1 or 2; or a prodrug and/or a pharmaceuticallyacceptable salt thereof; with the proviso that the compound of formula Ihas a minimum inhibition concentration of 32 μg/mL or less against atleast one of the organisms selected from the group consisting ofStreptococcus pneumoniae, Staphylococcus aureus, Staphylococcusepidermidis, Enterococcus faecalis, Enterococcus faecium, Haemophilusinfluenzae, Moraxella catarrhalis, Escherichia coli, Bacteroidesfragilis, Bacteroides thetaiotaomicron, and Clostridium difficile.
 6. Acompound selected from the group consisting of:4-Pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-propyl]-amide;4-Pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Hydroxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-piperidine-2-carboxylic acid{2-methyl-1-[3,4,5-trihydroxy-6-(2,2,2-trifluoro-ethylsulfanyl)-tetrahydro-pyran-2-yl]-propyl}-amide;4-Pentyl-pyrrolidine-2-carboxylic acid[1-(6-butoxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;4-Butyl-1-methyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;Phosphoric acidmono-(4,5-dihydroxy-6-{2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl)-amino]-propyl}2-propyl-tetrahydro-pyran-3-yl)ester; Hexadecanoic acid4,5-dihydroxy-6-{2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl)-amino]-propyl}-2-propyl-tetrahydro-pyran-3-ylester; Phosphoric acidmono-(4,5-dihydroxy-6-{2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl)-amino]-propyl}2-propyl-tetrahydro-pyran-3-yl)ester; Hexadecanoic acid4,5-dihydroxy-6-{2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl)-amino]-propyl}-2-propyl-tetrahydro-pyran-3-ylester;1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidine-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-pyrrolidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-pyrrolidine-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;4-Propyl-pyrrolidine-2-carboxylic acid{2-methyl-1-[3,4,5-trihydroxy-6-(2-hydroxy-ethyl)-tetrahydro-pyran-2-yl]-propyl}-amide;4-Propyl-pyrrolidine-2-carboxylic acid{2-methyl-1-[3,4,5-trihydroxy-6-(3-hydroxy-propyl)-tetrahydro-pyran-2-yl]-propyl}-amide;4-Propyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-pyrrolidine-2-carboxylic acid{2-methyl-1-[3,4,5-trihydroxy-6-(2-methylsulfanyl-ethyl)-tetrahydro-pyran-2-yl]-propyl}-amide;4-Propyl-pyrrolidine-2-carboxylic acid[1-(6-cyclopropylmethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide,or a prodrug and/or a pharmaceutically acceptable salt thereof.
 7. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of any oneof claims 1, 2 or
 5. 8. A method for the treatment of a microbialinfection in a mammal comprising administering to the mammal atherapeutically effective amount of a compound of any one of claims 1, 2or
 5. 9. A method for the treatment of a microbial infection in a mammalcomprising administering to the mammal a pharmaceutical composition ofclaim
 7. 10. The method according to claim 9, wherein the compound isadministered to the mammal orally, parenterally, transdermally,topically, rectally, or intranasally in a pharmaceutical composition.11. The method according to claim 9, wherein the compound isadministered in an amount of from about 0.1 to about 100 mg/kg bodyweight/day.
 12. A compound of Formula (I):

wherein: W is a nitrogen-containing ring:

 m is 0, 1, 2 or 3; wherein when m is 2, the nitrogen-containing ringmay optionally contain a double bond between the 4 and 5nitrogen-containing ring positions; wherein when m is 3, thenitrogen-containing ring may optionally contain one double bond betweeneither the 4 and 5 nitrogen-containing ring positions or between the 5and 6 nitrogen-containing ring positions; wherein thenitrogen-containing ring positions are consecutively numberedcounterclockwise beginning with “1” at the nitrogen; R¹ is selected fromthe group consisting of hydrogen, alkyl, substituted alkyl,hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy,cycloalkylalkyl, halo, alkylsulfanyl, and substituted alkylsulfanyl; R²and R³ are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl,substituted alkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷and the other is absent, or one of R² and R³ is ═CH₂ and the other isabsent; R⁶ is selected from the group consisting of hydrogen, alkyl,hydroxyalkyl, cycloalkyl, substituted alkyl, iminomethyl, —C(O)O-alkyl,—C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substituted aryl,—C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —(carboxamido)alkyl,(carbamoyl)alkyl, 5-alkyl-[1,3]dioxol-2-one-4-yl-methyl,5-alkyl-[1,3]dioxol-2-one-4-yl-methoxy-carbonyl, or —N(R⁶)— fragment ispart of the amidine, N-cyanoamidine, N-hydroxyamidine, orN-alkoxyamidine structure; R⁷ is H or alkyl; R⁹, which can be singly ormultiply substituted in the ring on the same or different carbons, isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl,substituted alkenyl, substituted oxygen, substituted nitrogen, halogen,phenyl, substituted phenyl, alkylsulfanyl, substituted alkylsulfanyl,substituted arylsulfanyl, heteroarylsulfanylalkyl,heterocyclicsulfanylalkyl, heteroarylsulfanyl, and heterocyclicsulfanyl,propylidene (═CHCH₂CH₃), azido, —(CH₂)_(n)—OH, —(CH₂)_(n)—NR⁴R⁵, andbranched chain isomers thereof wherein n is an integer of from 1 to 8inclusive and R⁴ and R⁵ are H or alkyl, alkoxyalkoxy, aryl, substitutedaryl, alkenyl, substituted alkenyl, and —S(O)_(q)R¹³ where q is aninteger equal to zero, one or two and R¹³ is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic, andwherein not more than one —S(O)_(q)R¹³ group is present on thenitrogen-containing ring; and wherein t=0-3; or a prodrug and/orpharmaceutically acceptable salt thereof; with the proviso excluding thefollowing compounds: the compounds when

 is a single bond and each R⁹ is hydrogen; and the compounds when

 is a single bond, R⁹ is substituted alkyl having a single substituentsaid single substituent is other than halo, oxygen, hydroxy, primaryamine, amine(secondary alkyl substituted by alkyl above), amine(tertiary alkyl substituted by alkyl as above), sulfur, —SH, phenyl, or—(CH₂)_(n)NR′R″ where n is an integer of from 1 to 8 and R′ and R″ arehydrogen or alkyl; and the compounds when

 is a single bond, R⁹ is halo.
 13. A compound of Formula (IA):

wherein: the

 represents a bond that may be a double bond or a single bond; R¹ isselected from the group consisting of —S-alkyl, —S-substituted alkyl,SMe, S-(2-hydroxyethyl), (heteroaryl)alkyl, hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy,cycloalkylalkyl, halo, and substituted alkylsulfanyl; R² and R³ areindependently hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substitutedalkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷ and the otheris absent; R⁶ is selected from the group consisting of hydrogen, alkylsubstituted alkyl (carboxamido)alkyl, (carbamoyl)alkyl, alkoxycarbonyl,(alkoxycarbonyl)alkyl, (alkoxycarbonylamino)alkyl, or —N(R⁶)— fragmentis part of the amidine, N-cyanoamidine, N-hydroxyamidine, orN-alkoxyamidine structure; R⁷ is selected from the group consisting ofhydrogen and alkyl; R⁹, which can be singly or multiply substituted inthe ring on the same or different carbons, is independently selectedfrom the group consisting of hydrogen, substituted alkyl, halo,substitutedalkenyl, alkenyl, (heteroaryl)alkenyl, and —S(O)_(q)R¹³ whereq is an integer equal to zero, one or two and R¹³ is selected from thegroup consisting of alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic; and wherein m=0-2; and wherein t=0-3; or pharmaceuticallyacceptable salts and/or prodrugs thereof; with the proviso excluding thefollowing compounds: the compounds when

 is a single bond and each R⁹ is hydrogen; and the compounds when

 is a single bond, R⁹ is substituted alkyl having a single substituentsaid single substituent is other than halo, oxygen, hydroxy, primaryamine, amine(secondary alkyl substituted by alkyl above), amine(tertiary alkyl substituted by alkyl as above), sulfur, —SH, phenyl, or—(CH₂)_(n)NR′R″ where n is an integer of from 1 to 8 and R′ and R″ arehydrogen or alkyl; and the compounds when

 is a single bond, R⁹ is halo.
 14. A compound of Formula (IA):

wherein: the

 represents a bond that may be a double bond or a single bond; R¹ isselected from the group consisting of —S-alkyl, —S-substituted alkyl,SMe, S-(2-hydroxyethyl), (heteroaryl)alkyl, hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy,cycloalkylalkyl, halo, and substituted alkylsulfanyl; R² and R³ areindependently hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substitutedalkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷ and the otheris absent; R⁶ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, (carboxamido)alkyl, (carbamoyl)alkyl, alkoxycarbonyl,(alkoxycarbonyl)alkyl, (alkoxycarbonylamino)alkyl, or —N(R⁶)— fragmentis part of the amidine, N-cyanoamidine, N-hydroxyamidine, orN-alkoxyamidine structure; R⁷ is selected from the group consisting ofhydrogen and alkyl; R⁹, which can be singly or multiply substituted inthe ring on the same or different carbons, is independently selectedfrom the group consisting of hydrogen, substituted alkyl, halo,substitutedalkenyl, alkenyl, (heteroaryl)alkenyl, and —S(O)_(q)R¹³ whereq is an integer equal to zero, one or two and R¹³ is selected from thegroup consisting of alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic; and wherein m=0-2; and wherein t=0-3; or pharmaceuticallyacceptable salts and/or prodrugs thereof; with the proviso excluding thefollowing compounds: the compounds when

 is a single bond and each R⁹ is hydrogen; and the compounds when

 is a single bond, R⁹ is substituted alkyl having a single substituentsaid single substituent is other than halo, oxygen, hydroxy, primaryamine, amine(secondary alkyl substituted by alkyl above), amine(tertiary alkyl substituted by alkyl as above), sulfur, —SH, phenyl, or—(CH₂)_(n)NR′R″ where n is an integer of from 1 to 8 and R′ and R″ arehydrogen or alkyl; and the compounds when

 is a single bond, R⁹ is halo.
 15. A compound of Formula (IA):

wherein: the

 represents a bond that may be a double bond or a single bond; R¹ isselected from the group consisting of —S-alkyl, —S-substituted alkyl,hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkoxy, substituted alkoxy and halo; R² and R³ are independentlyhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkoxy, substituted alkoxy, cyano, alkylsulfanyl, substitutedalkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷ and the otheris absent, or one of R² and R³ is ═CH₂ and the other is absent; R⁶ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, -(carboxamido)alkyl, (carbamoyl)alkyl,

or —N(R⁶)— fragment is part of the amidine, N-cyanoamidine,N-hydroxyamidine, or N-alkoxyamidine structure; R⁷ is selected from thegroup consisting of hydrogen and alkyl; R⁹, which can be singly ormultiply substituted in the ring on the same or different carbons, isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl,substituted oxygen, substituted nitrogen, halo, aryl, substituted aryl,alkenyl, substituted alkenyl, and —S(O)_(q)R¹³ where q is an integerequal to zero, one or two and R¹³ is selected from the group consistingof alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic; and whereinm¹=0-2; and wherein t=0-3; or pharmaceutically acceptable salts and/orprodrugs thereof; with the following provisos: A. that in the compoundsof formula (I) when

 is a single bond, m¹ is zero or one, R² and R³ are independentlyhydrogen, alkyl, hydroxy, fluoro, cyanoalkyl or one of R² and R³ is═NOR⁷ and the other is absent, or one of R² and R³ is ═CH₂ and the otheris absent, R⁶ is hydrogen, alkyl, hydroxyalkyl,—C(O)O-alkylene-cycloalkyl, —C(O)O-alkylene-substituted alkyl,—C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substitutedaryl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl,—C(O)O-heterocyclic, —C(O)O-substituted hetercyclic,—[C(O)O]_(p)-alkylene-heterocycle, —[C(O)O]_(p)-alkylene-substitutedheterocycle, where p is zero or one, and R⁷ is selected from the groupconsisting of hydrogen and alkyl; R⁹ is hydrogen, alkyl, substitutedalkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl, substitutedoxygen, substituted nitrogen, halo, phenyl, substituted phenyl,—(CH₂)_(n)—OH, —(CH₂)_(n)NR⁴R⁵, -alkylene-R^(a) where R^(a) is selectedfrom monofluorophenyl or monochlorophenyl, and branched isomers thereofwherein n is an integer from 1 to 8 inclusive and R⁴ and R⁵ are hydrogenor alkyl; and then R¹ is not —S-alkyl, B. in the compounds of formula(I), when

 is a single bond, R² and R³ are independently hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo,or one of R² and R³ is ═NOR⁷ and the other is absent, or one of R² andR³ is ═CH₂ and the other is absent, with the provisos that both R² andR³ are not hydrogen; when one of R² and R³ is halo, the other is nothydrogen or hydroxy; and when one of R² and R³ is hydroxy, the other isnot hydrogen or hydroxy; R⁶ is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, —C(O)O-alkyl, —C(O)O-substitutedalkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-heteroaryl,—C(O)O-substituted heteroaryl, -(carboxamido)alkyl, (carbamoyl)alkyl, or—N(R⁶)— fragment is part of the amidine, N-cyanoamidine,N-hydroxyamidine, or N-alkoxyamidine structure; R⁷ is selected from thegroup consisting of hydrogen and alkyl; and R¹ is selected from thegroup consisting of —S-alkyl, —S-substituted alkyl, hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy and halo; then at least one of R⁹ is other than hydrogen, alkyl,substituted alkyl, alkoxyalkoxy, cycloalkyl, substituted cycloalkyl,substituted oxygen, substituted nitrogen, halo, phenyl, substitutedphenyl, —(CH₂)_(n)—OH, —(CH₂)_(n)NR⁴R⁵, -alkylene-R^(a) where R^(a) isselected from monofluorophenyl or monochlorophenyl, and branched isomersthereof wherein n is an integer from 1 to 8 inclusive and R⁴ and R⁵ arehydrogen or alkyl, C. in the compounds of formula (I), when

 is a single bond, R² and R³ are independently hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, cyano, alkylsulfanyl, substituted alkylsulfanyl, hydroxy, halo,or one of R² and R³ is ═NOR⁷ and the other is absent, or one of R² andR³ is ═CH₂ and the other is absent, with the provisos that both R² andR³ are not hydrogen; when one of R² and R³ is halo, the other is nothydrogen or hydroxy; and when one of R² and R³ is hydroxy, the other isnot hydrogen or hydroxy; R⁷ is selected from the group consisting ofhydrogen and alkyl; and R¹ is selected from the group consisting of—S-alkyl, —S-substituted alkyl, (heteroaryl)alkyl, hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy and halo; R⁹ is independently selected from other than hydrogen,alkyl, substituted alkyl, alkoxyalkoxy, cycloalkyl, substitutedcycloalkyl, substituted oxygen, substituted nitrogen, halo, phenyl,substituted phenyl, —(CH₂)_(n)—OH, —(CH₂)_(n)NR⁴R⁵, -alkylene-R^(a)where R^(a) is selected from monofluorophenyl or monochlorophenyl, andbranched isomers thereof wherein n is an integer from 1 to 8 inclusiveand R⁴ and R⁵ are hydrogen or alkyl, then R⁶ is selected from the groupconsisting of substituted alkyl (other than monosubstituted heterocycleor substituted heterocycle),

(carboxamido)alkyl, and an —N(R⁶)— fragment that is part of an amidine,N-cyanoamidine, N-hydroxyamidine, or N-alkoxyamidine structure; wherein,as used in these provisos only, the following specific terms have thefollowing specific meanings: substituted alkyl refers to alkyl groupswherein one or more of the hydrogen atoms has been replaced by ahalogen, oxygen, hydroxy, amine (primary), amine (secondary-alkylsubstituted by alkyl as above), amine (tertiary-alkyl substituted byalkyl as defined above), sulfur, —SH or phenyl), substituted cycloalkylrefers to cycloalkyl substituted with an alkyl group, wherein alkyl isas defined above or a group wherein one or more of the hydrogen atomshas been replaced by a halogen, oxygen, hydroxy, amine (primary), amine(secondary-alkyl substituted by alkyl as above), amine (tertiary-alkylsubstituted by alkyl as defined above), sulfur, —SH or phenyl,substituted oxygen refers to the group —OR^(d) where R^(d) is alkyl,haloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,allkenyl, cycloalkyl, and substituted cycloalkyl, substituted nitrogenor amino refers to the group —NR^(a)R^(b) wherein R^(a) and R^(b) areindependently hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl, substituted aryl refers to an aryl ringsubstituted with one or more substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, halo, alkoxy, acyloxy, amino,hydroxy, carboxy, cyano, nitro, alkylthio and thioalkyl where alkyl thiorefers to the group —S-alkyl and thioalkyl refers to an alkyl grouphaving one or more —SH groups, and substituted heteroaryl refers to aheteroaryl ring substituted with one or more substituents selected fromthe group consisting of alkyl, alkenyl, alkynyl, halo, alkoxy, acyloxy,amino, hydroxy, carboxy, cyano, nitro, alkylthio and thioalkyl wherealkyl thio refers to the group —S-alkyl and thioalkyl refers to an alkylgroup having one or more —SH groups.
 16. The compound of any of theclaims 12-15 wherein the nitrogen-containing ring in Formulas (I) and(IA) is selected from:


17. A compound of Formula (IB):

wherein: R¹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl; R² and R³are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl,substituted alkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷and the other is absent; R⁶ is H, alkyl, or hydroxyalkyl; R⁷ is H oralkyl; R⁹, which can be singly or multiply substituted in the ring onthe same or different carbons, is independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, substituted oxygen, substituted nitrogen,halogen, phenyl, substituted phenyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—NR⁴R⁵,and branched chain isomers thereof wherein n is an integer of from 1 to8 inclusive and R⁴ and R⁵ are H or alkyl; and m is 1 or 2; or prodrugsand/or pharmaceutically acceptable salts thereof.
 18. A compound ofFormula (II):

wherein: W is a nitrogen-containing ring:

 m is 0, 1, 2, or 3; wherein when m is 2, the nitrogen-containing ringmay optionally contain a double bond between the 4 and 5nitrogen-containing ring positions; wherein when m is 3, thenitrogen-containing ring may optionally contain one double bond betweeneither the 4 and 5 nitrogen-containing ring positions or between the 5and 6 nitrogen-containing ring positions; wherein thenitrogen-containing ring positions are consecutively numberedcounterclockwise beginning with “1” at the nitrogen; R¹ is selected fromthe group consisting of hydrogen, alkyl, substituted alkyl,hydroxyalkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy,cycloalkylalkyl, halo, alkylsulfanyl, and substituted alkylsulfanyl; R²⁰and R²¹ are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl,substituted alkylsulfanyl, hydroxy, halo, or one of R²⁰ and R²¹ is ═NOR⁷and the other is absent, or one of R²⁰ and R²¹ is ═CH₂ and the other isabsent; or R²⁰ and R²¹ taken together are cycloalkyl, aryl, orheterocyclic group; R⁶ is selected from the group consisting ofhydrogen, alkyl, hydroxyalkyl, cycloalkyl, substituted alkyl,iminomethyl, —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, -(carboxamido)alkyl, (carbamoyl)alkyl,5-alkyl-[1,3]dioxol-2-one-4-yl-methyl,5-alkyl-[1,3]dioxol-2-one-4-yl-methoxy-carbonyl, or —N(R⁶)— fragment ispart of the amidine, N-cyanoamidine, N-hydroxyamidine, orN-alkoxyamidine structure; R⁷ is H or alkyl; R⁹, which can be singly ormultiply substituted in the ring on the same or different carbons, isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl,substituted alkenyl, substituted oxygen, substituted nitrogen, halogen,phenyl, substituted phenyl, alkylsulfanyl, substituted alkylsulfanyl,substituted arylsulfanyl, heteroarylsulfanylalkyl,heterocyclicsulfanylalkyl, heteroarylsulfanyl, and heterocyclicsulfanyl,propylidene (═CHCH₂CH₃), azido, —(CH₂)_(n)—OH, —(CH₂)_(n)—NR⁴R⁵, andbranched chain isomers thereof wherein n is an integer of from 1 to 8inclusive and R⁴ and R⁵ are H or alkyl, alkoxyalkoxy, aryl, substitutedaryl, alkenyl, substituted alkenyl, and —S(O)_(q)R¹³ where q is aninteger equal to zero, one or two and R¹³ is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic, andwherein not more than one —S(O)_(q)R¹³ group is present on thenitrogen-containing ring; or a prodrug and/or pharmaceuticallyacceptable salt thereof.
 19. A compound selected from the groupconsisting of: 4-(Thiophen-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylicacid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(4-Fluoro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(4-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(Pyridin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(Pyrazin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Butylsulfanyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3,3-Difluoro-allyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Pyridin-4-yl-allyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Pyridin-4-yl-propyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Methoxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(1H-Imidazol-2-ylnethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Formylamino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Amino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Cyclohexyloxy-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;{2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidin-1-yl}-aceticacid methyl ester;1-Methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[3-(Furan-2-ylmethylsulfanyl)-propyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[3-(Thiophen-2-ylsulfanyl)-propyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Methoxyimino-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[2-(4-Ethyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Ethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Ethoxyimino-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Pyrrol-1-ylmethyl-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid 9H-fluoren-9-ylmethyl ester;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid ethyl ester; 4-(3-Cyano-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid phenyl ester;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid phenyl ester;4-(2-[1,2,3]Triazol-1-yl-ethyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propylidene-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;and 4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Ethylsulfanyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(4-Fluoro-phenylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Butylsulfanyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3,3,3-Trifluoro-propylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2-Chloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Methyl-butylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[2-(2-Mercapto-ethoxy)-ethylsulfanyl]-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2,2,2-Trifluoro-ethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(Pyridin-4-ylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(4-Trifluoromethoxy-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(Thiophen-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(4-Fluoro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(4-Methyl-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(Pyridin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(Pyrazin-2-ylmethylsulfanyl)-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-hydroxy-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2,4-Dichloro-benzylsulfanyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Butylsulfanyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3,3-Difluoro-allyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-Carbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-Cyanomethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Pyridin-4-yl-allyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Pyridin-4-yl-propyl)-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Methoxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(1H-Imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Formylamino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Amino-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Cyclohexyloxy-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;{2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidin-1-yl}-aceticacid methyl ester;1-Methylcarbamoylmethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(2-[1,3]Dithiolan-2-yl-ethyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-Iminomethyl-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[3-(Furan-2-ylmethylsulfanyl)-propyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Imidazol-1-yl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[3-(Thiophen-2-ylsulfanyl)-propyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-imidazol-1-yl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[2-(4-Methyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Methoxyimino-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-[2-(4-Ethyl-thiazol-2-yl)-ethyl]-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Ethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Ethoxyimino-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Pyrrol-1-ylmethyl-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid 9H-fluoren-9-ylmethyl ester;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid ethyl ester; 4-(3-Cyano-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid phenyl ester;2-[2-Methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-piperidine-1-carboxylicacid phenyl ester;4-(2-[1,2,3]Triazol-1-yl-ethyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propylidene-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;3-(3-Cyclobutyl-propyl)-azetidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide4-(3-Difluoromethylsulfanyl-propyl)-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;and 4-(2-Cyclopropyl-ethyl)-piperidine-2-carboxylic acid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide20. A compound selected from the group consisting of: Phosphoric acidmono-(6-{2-chloro-1-[(5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl)ester; Phosphoric acidmono-(6-{2-chloro-1-[(5-fluoro-5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl)ester; Phosphoric acidmono-(6-{2-chloro-1-[(5-cyclopropylmethyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl)ester; Phosphoric acidmono-(6-{2-chloro-1-[(4-fluoro-4-propyl-piperidine-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-yl)ester; Hexadecanoic acid6-{2-chloro-1-[(5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-ylester, Hexadecanoic acid6-{2-chloro-1-[(5-fluoro-5-propyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-ylester; Hexadecanoic acid6-{2-chloro-1-[(5-cyclopropylmethyl-azepane-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-ylester; Hexadecanoic acid6-{2-chloro-1-[(4-fluoro-4-propyl-piperidine-2-carbonyl)-amino]-propyl}-4,5-dihydroxy-2-methylsulfanyl-tetrahydro-pyran-3-ylester.
 21. A compound selected from the group consisting of:2-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-propyl-azepane-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;2-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-fluoro-5-propyl-azepane-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;5-Fluoro-1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-5-propyl-azepane-2-carboxylicacid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;5-Cyclopropylmethyl-1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-azepane-2-carboxylicacid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-5-cyclopropylmethyl-azepane-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;2-[2-Chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-fluoro-4-propyl-piperidine-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;4-Fluoro-1-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-piperidine-2-carboxylicacid[2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide.22. A compound of Formula (IB):

wherein: R¹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, cycloalkylalkyl, halo, and substituted alkylsulfanyl; R² and R³are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, cyano, alkylsulfanyl,substituted alkylsulfanyl, hydroxy, halo, or one of R² and R³ is ═NOR⁷and the other is absent; R⁶ is H, alkyl, or hydroxyalkyl; R⁷ is H oralkyl; R⁹, which can be singly or multiply substituted in the ring onthe same or different carbons, is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,substituted oxygen, substituted nitrogen, halogen, phenyl, substitutedphenyl, —(CH₂)_(n)—OH, —(CH₂)_(n)—NR⁴R⁵, and branched chain isomersthereof wherein n is an integer of from 1 to 8 inclusive and R⁴ and R⁵are H or alkyl; and m is 1 or 2; or a prodrug and/or a pharmaceuticallyacceptable salt thereof; with the proviso that the compound of formula Ihas a minimum inhibition concentration of 32 μg/mL or less against atleast one of the organisms selected from the group consisting ofStreptococcus pneumoniae, Staphylococcus aureus, Staphylococcusepidermidis, Enterococcus faecalis, Enterococcus faecium, Haemophilusinfluenzae, Moraxella catarrhalis, Escherichia coli, Bacteroidesfragilis, Bacteroides thetaiotaomicron, and Clostridium difficile.
 23. Acompound selected from the group consisting of:4-Pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-propyl]-amide;4-Pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-piperidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;1-(2-Hydroxy-ethyl)-4-pentyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-piperidine-2-carboxylic acid{2-methyl-1-[3,4,5-trihydroxy-6-(2,2,2-trifluoro-ethylsulfanyl)-tetrahydro-pyran-2-yl]-propyl}-amide;4-Pentyl-pyrrolidine-2-carboxylic acid[1-(6-butoxy-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide;4-Butyl-1-methyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;Phosphoric acidmono-(4,5-dihydroxy-6-{2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl)-amino]-propyl}2-propyl-tetrahydro-pyran-3-yl)ester; Hexadecanoic acid4,5-dihydroxy-6-{2-methyl-1-[(4-pentyl-pyrrolidine-2-carbonyl)-amino]-propyl}-2-propyl-tetrahydro-pyran-3-ylester; Phosphoric acidmono-(4,5-dihydroxy-6-{2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl)-amino]-propyl}2-propyl-tetrahydro-pyran-3-yl)ester; Hexadecanoic acid4,5-dihydroxy-6-{2-methyl-1-[(4-propyl-pyrrolidine-2-carbonyl)-amino]-propyl}-2-propyl-tetrahydro-pyran-3-ylester;1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-pentyl-pyrrolidine-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;1-(5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-4-propyl-pyrrolidine-2-carboxylicacid[2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide;2-[2-Methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propylcarbamoyl]-4-propyl-pyrrolidine-1-carboxylicacid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester;4-Propyl-pyrrolidine-2-carboxylic acid{2-methyl-1-[3,4,5-trihydroxy-6-(2-hydroxy-ethyl)-tetrahydro-pyran-2-yl]-propyl}-amide;4-Propyl-pyrrolidine-2-carboxylic acid{2-methyl-1-[3,4,5-trihydroxy-6-(3-hydroxy-propyl)-tetrahydro-pyran-2-yl]-propyl}-amide;4-Propyl-pyrrolidine-2-carboxylic acid[2-methyl-1-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-propyl]-amide;4-Propyl-pyrrolidine-2-carboxylic acid{2-methyl-1-[3,4,5-trihydroxy-6-(2-methylsulfanyl-ethyl)-tetrahydro-pyran-2-yl]-propyl}-amide;4-Propyl-pyrrolidine-2-carboxylic acid[1-(6-cyclopropylmethyl-3,4,5-trihydroxy-tetrahydro-pyran-2-yl)-2-methyl-propyl]-amide,or a prodrug and/or a pharmaceutically acceptable salt thereof.
 24. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of any oneof claims 12-15 and 17-23.
 25. A method for the treatment of a microbialinfection in a mammal comprising administering to the mammal atherapeutically effective amount of a compound of any one of claims12-15 and 17-23.
 26. A method for the treatment of a microbial infectionin a mammal comprising administering to the mammal a pharmaceuticalcomposition of claim
 24. 27. A method according to claim 26 for thetreatment of a microbial infection caused by any of the followingbacterial pathogens: H. influenzae, E. faecalis, and E. faecium.
 28. Themethod according to either claim 26 or 27, wherein the compound isadministered to the mammal orally, parenterally, transdermally,topically, rectally, or intranasally in a pharmaceutical composition.29. The method according to either claim 26 or 27, wherein the compoundis administered in an amount of from about 0.1 to about 100 mg/kg bodyweight/day.